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Review Articles

Immunology and ovarian cancers

Lee, Wen-Linga,b,c; Wang, Peng-Huic,d,e,*

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Journal of the Chinese Medical Association: May 2020 - Volume 83 - Issue 5 - p 425-432
doi: 10.1097/JCMA.0000000000000283
  • Open

Abstract

1. INTRODUCTION

Epithelial ovarian cancer (EOC) is one of the highest lethal female cancers not only in the United States but also in Taiwan.1–3 Despite the ongoing process in its research and treatment, the health and economic burden is continuously increasing worldwide, partly because of its vague symptoms or free of symptoms, and short or unknown duration.4–7 EOC is often and easily misdiagnosed with a resultant delay diagnosis.4–7

The current treatment of EOC can be separated into two categories. One is the combination of primary debulking surgery (also called primary cytoreductive surgery) and the following postoperative platinum-/paclitaxel–based chemotherapy.8–13 The other is also the combination of chemotherapy and debulking surgery but the treatment schedule is an initial chemotherapy (neoadjuvant chemotherapy), the following interval debulking surgery (also called interval cytoreductive surgery) and a final chemotherapy, which is similar to the sandwich, including chemotherapy-operation-chemotherapy).14–18 This approach is reported to have the lower risk of immediate operation-related morbidity and mortality; therefore, it is more and more popular for the treatment of women with far-advanced staged EOC recently.14,15,18

Under this most popular and well-accepted standard therapy, the outcome is still disappointing. In fact, nearly all patients can achieve complete remission under this aggressive and active therapy, regardless whether they are advanced diseases or not; however, the majority will relapse and finally die within several years after initial treatment. The literature review shows the median progression-free survival (PFS) ranging from 16 to 21 months and the median overall survival (OS) ranging from 32 to 57 months.4 All suggest that the new modalities are urgently needed to enhance the therapeutic effects and subsequently increase PFS and OS.

A promising advance in EOC therapy includes (1) altered delivery method of chemotherapeutic agents (the use of intraperitoneal route in place of intravenous route); (2) changed dose and interval of chemotherapy administration (dose-dense chemotherapy); (3) intraperitoneal hyperthermia treatment; and (4) adding new agents (small molecules, monoantibodies, and others) into the conventional therapy, based on the following mechanisms, such as (a) targeting the specific cancer-specific antigens, (b) attacking the underlying repair system of cancer cells, (c) blocking the nutrition or oxygen supply (for example, antiangiogenic drugs), (d) changing the interaction between cancer cells and surrounding cells, (e) altering or modifying behaviors of cancer cells, (f) enhancing immune clearance ability (for example, immune checkpoint inhibitors [ICIs], immune system modulators), and (g) enhancing the therapeutic effect of the original chemotherapy.19–49 These latter new agents can be used in the combination of original chemotherapy or alone, based on their targeted sites and mechanisms.38–49 All represent a paradigm shift in cancer treatment. This article serves to update emerging data from research articles or trials evaluating the impact of immunotherapy on EOC and briefly introduce the advance and development of therapeutic interventions with the goal to improve outcome of patient with EOC.

2. OVARIAN CANCER AND AN ESCAPE FROM IMMUNE RESPONSE

Conventionally, according to the histology, EOC is classified as serous, endometrioid, clear cell, mucinous, and other subtypes.50–58 Serous carcinoma can be further separated into high grade and low grade, based on distinct histological features and molecular genetics.58 For a convenient way of conceptualizing different mechanisms of tumorigenesis, the dualistic classification of EOC into “type I” and “type II” is also popular in the research setting.24,58–68 However, this dualistic classification may conflict with recent molecular insights of the etiology of EOC. For example, endometriosis-associated EOC (clear cell carcinoma) is traditionally classified as “type I,” but it is absence of assuming an indolent course or type I.62,68,69 By contrast, type II EOC, such as a serous cell carcinoma, accounting >70% of all malignant ovarian tumor is considered to arise from the distal fallopian tube and shows distinct genetic profiling, such as over 96% of TP53 mutations and much frequent BRCA mutations.58,65,67,68

Due to advanced development of bioinformatics, EOC can present various alternations of biological and molecular factors, dysfunctional expression or mutation of genes, dysregulation of host immune responses, oxidative stress (the release of reactive oxygen species [ROS]), traumatic effect of organs (ovulation), activation of oncogenes or inactivation of suppressor genes, reactions to growth factor, and cytokines in the tumor microenvironment (TME).42,43,70–72

Immunosurveillance is supposed that tumor cells express new antigenic targets that can be recognized and eradicated by host immune response.73 Host immune system continues the immune-editing process, which involves an interaction between tumor and innate or adaptive immune response because it should reflect a balance of selective pressure to protect the host against cancer development while simultaneously influencing tumor evolution and immunogenic phenotype.73 A successful elimination of tumor results in healthy and tumor-free host.

By contrast, a propagation of tumor variants with the capacity to escape or ultimately evade immune clearance results in the development of cancer in host, which can be mediated by many pathways, such as the expression of immune checkpoint programmed cell death protein (PD-1)/programmed cell death protein ligand 1 or 2 (PD-L1 or PD-L2), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), B7-H3, B7-H4, indoleamine 2,3, dioxygenase (IDO), nitric oxide synthase 2, as well as arginase-1 (ARG-1), and the release of ROS, peroxynitrite, and factors or cytokines, including transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), interleukin (IL)-1, prostaglandin E2 (PGE2), released by EOC cells and/or surrounding immune cells, contributing to inhibited tumor-infiltrating immune cells, such as tumor-infiltrating lymphocyte (TIL) function, natural killer (NK) cell function, kill cluster of differentiation 8+ (CD8+) effector TILs or macrophage function.70–72 Cells of the immune system can be derived from various pronator cells within the bone marrow that differentiate into a diverse range of subpopulations that ultimately compose all lineages of the hematopoietic compartments. The followings are briefly reviewed based on the specific immune cell types, which are related to initiation, growth, and metastases of tumors.

3. NATURAL KILLER CELLS

NK cells, one of innate immune cells, are a unique lymphocyte subset able to detect and rapidly kill abnormal cells, such as virus-infected cells, cancer, and foreign cells hazardous to the host, without prior sensitization and controlled tightly by inhibitory receptors (CD94/natural killer group [NKG] 2A) and activating NK receptors (CD94/NKG2C).73 The inhibitory killer Ig-like receptors (KIRs), recognizing allotypic determinants shared by group human leukocyte antigen (HLA) class-I alleles, and by the CD94/NKG2A heterodimer, specific for the nonclassical HLA-E molecule are main inhibitory inhibitors, and also based on 4 specific epitopes, further are classified as KIR2DL1 (HLA-C2 epitope), KIR2DL2/L3 (LA-C1), KIR3DL1 (HLA-B or HLA-A), and KIR3DL2 (HLA-A*03 and HLA-A*11).74

NK cells are grossly categorized into two populations based on CD16 and CD56 expression.70 The most immature CD56bright NK cell subset contains CD94/NKG2A, and more mature CD56dim loses NKG2A and acquires KIR receptors.74 CD56bright/CD16 functions to produce cytokines in the circulating blood, and CD56dim/CD16+ performs cytotoxicity in the tissues.70

NK cells recognize targets based on their expression of stress-induced ligands, upregulated on the cell surface consequent to deoxyribonucleic acid (DNA) damage and heat shock and in response to stimulation or inhibition by environmental factors, mainly as cytokines (IL-2, IL-10, IL-12, IL-15, IL-21, TGF-β, and interferon γ [IFNγ]) or chemokines (CD48, CD155, CD112, NKG2D ligands, granulocyte-macrophage colony-stimulatory factor [GM-CSF], C-C Motif Ligand 5 [CCL5], major histocompatibility complex [MHC] class 1 polypeptide-related sequence-A/B [MIC-A/B], UL-16 binding protein [ULBP]1-6, B7-H6, cytomegalovirus pp65 tegument protein, BCL2-associated athanogene 6, heparin sulfate, proliferating cell nuclear antigen, platelet-derived growth factor, mixed-lineage leukemia-5 [MLL-5], viral hemagglutinins, complement factor P, tumor necrosis factor [TNF]-related apoptosis-inducing ligand, MHC-C2 group ligands, MHC-C1 group ligands, MHC-B alleles with the Bs4 motif, and PD-1).70

However, the correlation between NK cells and outcome of EOC patients is still debated. Some studies found the worse prognosis in EOC patients if NK cells were apparent in ascites, but by contrast, the better outcome was found if NK cells were apparent in the peripheral blood, suggesting the role of NK cells is much complicated, and the tumor suppression or promotion might be varied by different pathway.75 Based on the aforementioned phenomenon, to restore NK cells activity, the several strategies can be applied and mainly based on manipulation of the function of inhibitory receptors.76 Besides the specific to KIRs, other proteins or targets (for example, anti-PD-1 inhibitors) are also involved.

The combination of various kinds of antibody-mediated blocking of multiple inhibitory checkpoints or other signaling pathways, such as epidermal growth factor (EGF)/EGF receptor on NK cells, including anti-NKG2A (monalizumab, IPH2201), anti-pan-KIR2D (lirilumab), anti-PD-1 (nivolumab, pembrolizumab, or tislelizumab), anti-PD-L1 (durvalumab, atezolizumab, avelumab), anti-CTLA-4 (ipilimumab), anti-T cell immunoglobulin- and mucin domain-containing molecule (anti-TIM-3, Sym023), anti-lymphocyte activation gene 3 (anti-LAG-3, Sym022 or BMS-98601), and anti-T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (anti-TIGIT, OMP-313M32 or BGB-A217 or MTIG7192A) as well as CD96 by triggering their ability to kill tumor cells, is likely to facilitate the uptake of novel/additional tumor antigens by antigen-presenting cells and subsequent massive recruitment of antigen-specific T lymphocytes.74,76–85 Some of them have entered into clinical trials, either phase I/II or phase III, including NCT01968109, NCT02054806, NCT02452424, NCT02459301, NCT02526017, NCT02657889, NCT02671435, NCT02718911, NCT 02873962, NCT03250832, NCT03489369, NCT03522246, NCT03532451, NCT038100, NCT04047862, etc.74,86

4. MACROPHAGES

Similar to NK cells, macrophages, originated from monocytes produced from bone marrow hematopoietic stem cells, are one of the crucial components of innate immune response, involving pathological response and in-tissue homeostasis.71,87 Macrophage with a strong plasticity and functional diversity can be polarized into two mainstreams, classically activated macrophage (M1, for example, with IL-12high, IL-23high, and IL-10low) and alternatively activated macrophage (M2, for example, with IL-12low, IL-23low, and IL-10high as well as presence of mannose receptor and scavenger receptor A), and these two mainstreams can be cross-over each other.71,87–92 M1 macrophages, exhibiting proinflammatory properties with capacity for antigen presentation, secreting proinflammatory cytokines, such as TNF-α, IL-1, and CCL2, CCL3, CCL5, C-X-C Motif Chemokine Ligand 8 (CXCL8, IL-8), CXCL9, CXCL11, CXCL16, and highly producing IL-1β, IL-6, IL-12, IL-23, nitric oxide (NO), reactive oxygen intermediates, expressing matrix metalloproteinase 12 (MMP12), and being accompanied with T helper cell 1 (Th1)-mediated immune response, have bactericidal, immune stimulatory, and antitumoral activities.71,86,91

By contrast, M2 macrophages exhibit anti-inflammatory properties, contributing to an increased parasite containment, and enrichment of a TME for cancer development, growth, and metastases, such as an increased angiogenesis, an increased tissue remodeling, and a suppression of antitumor immunity.71,87,92 The M2 phenotypes can further be separated into four forms, including M2a (IL-4 and/or IL-13 induction, promoting tissue repair through the secretion of extracellular matrix), M2b (induced by immune complex, agonists of Toll-like receptors [TLRs], or IL-1 receptor), M2c (IL-10 or glucocorticoid hormone induction, with a resultant suppression of immune response and tissue remodeling), and M2d (induced by adenosine, leukemia inhibitory factor, and IL-6, with enhancement of tumor survival, secreting a lot amount of VEGF and IL-10).71,87,92

It is reported that macrophages, including tumor-associated macrophages (TAMs) are one of the most abundant immune cells in EOC patients, not only within the tissue but also ascites, and M2 phenotypes (positive CD204, CD206, CD163, and IL-10) were predominent.71,87,92 Evidence showed that a high density of CD163+ M2 macrophages in EOC patients is correlated with poor OS. Similar to CD163, the M2 marker CD206 is also associated with poor prognosis in EOC patients. Low M1/M2 ratio contributes to worst outcome, but high M1 (HLA-DR, inducible nitric oxide synthase [iNOS])/M2 (CD163, VEGF) ratios in ovarian tissue are associated with better outcome.93–96

A meta-analysis further confirmed that higher M1/M2 ratio in EOC tissues was associated with a favorable OS (hazard ratio [HR] = 0.45, 95% confidence interval [CI] = 0.28–0.71) and was also used to predict the better PFS (HR = 0.49, 95% CI = 0.27–0.89); elevated intraislet M1/M2 TAMs ratio showed a positive correlation for OS (HR = 0.51, 95% CI = 0.26–0.99); by contrast, a high density of CD163+ TAMs was associated with worse PFS (HR = 2.16, 95% CI = 1.41–3.31); higher CD163+/CD68+ ratio was also associated with worse PFS (HR = 3.22, 95% CI = 1.81–5.76) and correlated with advanced tumor size-node status-metastatic status stage, suggesting that TAMs act as a “bridge” or mediator during the initiation and/or promotion of cancer by interacting with cancer cells.97 TAMs sustain intraperitoneal dissemination of EOC through CCL18 secretion and enable the trafficking of immune suppressive T regulatory cells (Tregs) to the EOC through CCL22 secretion. In addition, TAMs mediated through VEGF secretion and expression of B7-H4 and PD-L1 result in activation of angiogenesis process and suppression of T cell cytotoxicity.98

Macrophage subpopulations with identifiable markers may be an attractive therapeutic target for immunotherapy, contributing to at least four strategies to overcome the role of a “bridge” of TAMs, including disturbing TAM cell survival (TAM depletion), inhibiting the recruitment of TAMs, editing M2-like TAMs to repolarize M1-like TAMs, delivering molecules into TAMs to enhance reactivation, using anti-immune checkpoint molecules to restore function of macrophages, using microRNAs or modifying epigenetic regulation to target macrophage to restore their function (reprogramming of TAMs).87 For example, trabectedin possesses the cytotoxicity to TAMs.99 Targeting colony-stimulation factor 1 (CSF1)-CSF1 receptor (CSF1R) signaling pathway can be used as an effective method to result in depletion of TAMs.87 Combination of CSF1R antagonist with CD40 agonist drives repolarization from M2 to M1.87 Alemtuzumab attacks and damages TAMs.100 The use of polymer nanoparticles loaded with cisplatin enhances the antitumor effect of macrophages.101 Paclitaxel can repolarize M2 to M1 macrophages mediated by TLR4 signaling pathway.102 The targeted sites for epigenetic regulation can be based on the mechanisms of epigenetics, such as posttranslational modification, β-N-glycosylation, sialylation, methylation, acetylation, phosphorylation, and carbonylation of histones that bind DNA.87 For example, histone deacetylase 3 (HDAC3) can act as a brake for M2 polarization while enhancing M1 response,87 and the development of HDAC inhibitor may also be promising on the therapy for EOC patients.103

There are many clinical trials using the different strategy to enhance the therapeutic effects on patients with EOC, which have been demonstrated in the previous section. Some targeted sites, such as a CCL2 antibody (carlumab), were also tested in the combination with chemotherapy (NCT01204996).87

5. MYELOID-DERIVED SUPPRESSOR CELLS

Myeloid-derived suppressor cells (MDSCs), characterized by the expression of the myeloid markers CD11b, CD33, and low or absent HLA-DR, display immune suppressive properties against innate and adaptive immunity and can be divided into three categories, including early-stage MDSC (e-MDSC, characterized as Lin, including CD3, CD14, CD19, and CD56, which expresses HLA-DR/CD33+/CD11b+/CD14), monocystic MDSC (M-MDSC, expressing CD14), and granulocytic MDSC (G-MDSC) or polymorphonuclear MDSC (PMN-MDSC, expressing CD15) subsets.104–111

Several pathological conditions, including chronic infection, inflammation, trauma, and malignancy, the associated cytokine milieu (GM-CSF, G-CSF, M-CSF, stem cell factor, CCL2, CXCL2, CXCL8/IL-8, IL-1β, IL-6, IL-10, IL-18, TGF-β, VEGF, PG E2, cyclooxygenase-2 [COX-2], S100A8, S100A9, and TNF-α) is known to trigger emergency myelopoiesis which stimulates the proliferation of these immature myeloid cells (IMCs).106,107 MDSCs representing a compensatory response to chromic immune stimulation preventing the over-stimulation of immune effector cells that can result in bystander damage. However, this alternation in the immunologic milieu may facilitate promotion of tumor growth, and dissemination, and the immune paresis of cancers, which may be a significant obstacle for the development of effective therapies against cancer.104–111 The Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway and phosphatidylinositol 3-kinase [PI3K]/Akt signal are reported to play a critical role in mediating both the expansion of MDSCs and their function in suppressing immune cells.108

The action of MDSCs is shown below. MDSCs secrete high levels of ARG-1 with resultant l-arginine depletion, directly inducing lymphocyte suppression.108 MDSCs generate oxidative stress by increasing levels of ROS and iNOS with resultant overproduction of nitrogen species, such as peroxynitrite, hydrogen peroxide (H2O2), and NO, which suppresses T cell function mediated by Jak/STAT signaling pathway, reducing MHC expression, inducing T cell apoptosis, promoting the loss of theta expression, and the nitration and desensitization of the T cell receptor (TCR).108 MDSCs secrete IDO to polarize antigen-presenting cells toward a tolerance phenotype.108 MDSCs express high levels of PD-L1 and Galectin 3 capable of inducing T cell apoptosis.108 MDSCs enhance the stemness of EOC cells as well as induce epithelial-mesenchymal transition, secrete a lot amount of MMP9 to increase the bioavailability of VEGF, and have the potential to differentiate into endothelial-like cells.107

Based on the aforementioned mechanisms, there are several strategies to target MDSCs, including prevention of MDSC formation, induction of MDSC differentiation, blockade of MDSC expansion, blockade of MDSC activation, blockade of MDSC recruitment, blockade of MDSC function, and depletion of MDSCs.108 There are many agents available for the purpose to target MDSCs, which include Curcumin derivatives, tyrosine-kinase inhibitors (Sunitinib), Tasquinimod, Vemurafenib, vitamins (all-trans retinoic acid and vitamin D3), icariin derivatives, a novel polysaccharide, MPSSS, from Lentinus edodes (MPSSS polysaccharide), bevacizumab, anti-IFNγ antibody, GW2580, CSF1R antibody, COX-2/PGE2 receptor inhibitors, acetylsalicylic acid, zoledronic acid, phosphodiesterase-5 inhibitors (Sildenafil and Tadalafil), N-hydroxyl-l-arginine, nitroaspirin, N-acetyl cysteine, CpG oligodeoxynucleotides, bardoxolone methyl, withaferin A, Gr-1 antibody, IL4Rα aptamer, HDAC1 inhibitors (Entinostat), chemotherapeutic agents (gemcitabine, 5-fluorouracil, and paclitaxel), and peptibodies.108–114

6. NEUTROPHILS

Neutrophils might be one of the early immune responses to all injuries, including cutting wound, burn wound, pathogen or physiology or chemistry inducing trauma.115–117 However, the functions of neutrophils might much more go far beyond the elimination of microorganisms, since evidence has shown that neutrophils are highly versatile and sophisticated cells,118 and hundreds of reports have clearly documented functional and phenotypic heterogeneity of neutrophil.110,118–120 The discrimination between tumor-associated neutrophils (or called N2 neutrophils or similar to PMN-MDSC, as shown above) and neutrophils subpopulations is still debated.110

Similar to subpopulation of M1/M2 in macrophages, N2-type neutrophils represent a group of pathologically activated neutrophils (either recruited from peripheral PMN-MDSCs or peripheral blood-derived neutrophils with low density [tumor-promoting low-density neutrophils (LDNs)] under the influence of TGF-β in the TME), eliciting powerful tumor-promoting mechanisms and proinflammatory functions, such as upregulation of ARG-1 expression and angiogenesis, inducing vascular damage via their enhanced ability to release inflammatory molecules and autoantigens as well as neutrophil extracellular traps (NETs, resulting from the extrusion of nuclear DNA together with antimicrobial proteins), and enhancement of metastases; by contrast, N1-type neutrophils (high-density neutrophils [HDNs]) display functions of classical neutrophils like phagocytosis, Ab-dependent cytotoxicity and recruitment of leukocytes.110,115 Besides LDNs and HDNs of neutrophils, normal-density neutrophils (NDNs), including subsets of CD15+CD16low and the CCL2-producing subsets, are reported to play an inhibitory role on the T cell proliferation through different mechanisms.115

The role of neutrophils on the prognosis of tumor is often negative.115 Evidence supports the strong correlation between elevated numbers of tumor infiltrating and/or peripheral blood neutrophils, as well as elevated blood neutrophil/lymphocyte ratios (NLRs), and worst prognosis of various kinds of cancers, and other chronic diseases.121–130 Neutrophils have been considered to be the primary source of circulating VEGF and are also associated with increasing production of TNF, IL-1, IL-6, providing a favorable TME for cancer survival and proliferation.126 In ovarian cancer, high preoperative NLR is significantly associated with poor survival.129,130 One meta-analysis that involved 12 studies containing 3854 patients concluded that elevated pretreatment NLR levels were significantly correlated with advanced cancer stage (odds ratio [OR] = 2.32, 95% CI = 1.79–3.00), higher serum CA125 (OR = 3.33, 95% CI = 2.43–4.53), more extensive ascites (OR = 3.54, 95% CI = 2.31–5.42) as well as less chemotherapeutic response (OR = 0.53, 95% CI = 0.40–0.7), contributing to shorter PFS (HR = 1.63, 95% CI = 1.27–2.09), and poorer OS (HR = 1.69, 95% CI = 1.29–2.22).126

7. T LYMPHOCYTES

The role of T cell-mediated immune responses in solid tumors is well established and has become the brightly targeted sites, specifically with the advent of ICI. Maturation of naive T lymphocytes (naive T cells) is strictly regulated in the thymus, where the TCR repertoire is shaped by somatic gene rearrangement and selection processes, resulting in a T cell pools, which requires both the stimulation of the TCR by MHC-peptide complex (signal 1, mainly on MHC1) and costimulatory receptors (signal 2) with the corresponding ligands on antigen-presenting cells (APCs), and these cosignaling receptors either positively (costimulatory) or negatively (coinhibitory) regulate T cell stimulation-derived signals and direct T cell activation, expansion, and differentiation.131–133 A costimulatory pathway, CD28:B7 axis as an example, is a combination of CD28 on T cells and its ligand B7-1 or B7-2 on activated APCs via MHCI on amplifying TCR signaling, leading to T cell to become fully functional, and continue proliferation, expansion, and persistence (CD8+ cytotoxic T lymphocytes CTLs) and IL-2 production.131,132

Furthermore, subpopulations include the phenotype of naive (TregN), stem cell memory-like (TregSCM), central memory (TregCM), and effector memory (TregEM) and terminally differentiated effector cells (TregTEMRA), based on their surface expression of CD62L/CCR7, CD45RA/RO, and CD95.134 The other CD4+ T cells, recognizing epitopes complex via MHCII on the surface of APCs, possess their helper function in sustaining CD8+ T cell response and activating innate immunity.132 There are many costimulatory receptors found, including inducible costimulatory molecule search, CD226, OX-40, 4-1BB, and glucocorticoid-induced TNF receptor related gene, and other coinhibitory receptors, such as CTLA-4, PD-1, TIM-3, T cell immunoglobulin [TIGIT] and TIM domain), and LAG-3, and both contribute to several T cell subsets available, including activated T cells, Tregs, and exhausted T cells.131

During the T cell response to cancer, tumor antigen-experienced lymphocytes might undergo activation and differentiation into effector and memory fates.131 It is reported that CD8+ T cells (TILs) might be correlated with a favorable clinical outcomes in cancers,130,135 while increases in immunosuppressive Tregs are associated with poor outcomes.135 CD4+ T cells might enhance Th1-type pathway to have a direct antitumor role via the secretion of IFNγ or TNF-α.131 In the study by Pinto et al,130 intraepithelial CD4+ cells are associated to an increase in both PFS and OS in patients with high-grade serous EOC. However, T cell exhaustion often occurs in tumor immunity, and these T cells, mainly CD4+CD25+FoxP3+ tTregs often have high expression of coinhibitory receptors, such as CTLA-4, PD-1, TIM-3, or LAG-3.131

The T cell plays a new era of cell and gene therapy in solid tumor, because the chimeric antigen receptor (CAR) technology has been continuously developed.135 Trials of CAR-T cells in EOC are ongoing and some are applied into peritoneum cavity directly (NCT03585764; NCT02498912).136

8. B LYMPHOCYTES

The multifaced effects of cancer-associated T lymphocytes have been much extensively evaluated, as shown above, and however, the contribution of B-lymphocytes to tumor immune responses is less well understood.137–139 B-cells are continuously produced throughout life from hematopoietic stem cells in the bone marrow and undergoing the development or differentiation process in B-cell follicles within secondary lymphoid organs, where germinal centers develop in response to antigen stimulation, and all processes are tightly regulated through the B-cell receptor (BCR).137 B-cells can be separated into naive B-cells (CD20+, CD19+, CD138, CD95, CD27), long-lived memory B-cells (CD20+, CD19+, CD138, CD95+, CD27+), long-lived plasma cells (CD20, CD19+, CD138+, CD95+, CD27+), and regulatory B (Breg)-cells.138

The prognostic significance of B-cell on EOC is not clear. Infiltration of CD19+ B-cells in the omentum and high percentage of CD19+ B-cells or CD138+ B-cells in EOC patients were reported to be associated with worse prognosis.139–142 By contrast, presence of CD20+ B-cells seemed to be correlated with good prognosis.143–145 Many studies focused on B-cell components of TIL in patients with EOC, and majority of them suggested Bregs within the TEM often play an immunosuppressive role and subsequently contribute to tumor progression and bad outcome in patients with EOC.138 However, only few investigators were interested in the role of B-cells on cancer, contributing to unknown scenario of B-cells in EOC.138

9. THE PERSPECTIVE

The final pathway either by immune clearance (antitumor effect) or by immune tolerance (tumor promotion) is dynamic and involves interaction between cancer cells and various immune cells.146 Study found that the connection between immune microenvironment variation and malignant spread is very complicated and associated with prognosis. This malignant-immune interface of EOC is one of the targeted sites for the treatment of patients with EOC.

ACKNOWLEDGMENTS

This study was supported in part by grants from the Ministry of Science and Technology (MOST 106-2314-B-075-061-MY3) and the Taipei Veterans General Hospital (Grants VGH108C-085 and V109C-108), Taipei, Taiwan. The authors also appreciate very much financial support from the Female Cancer Foundation, Taipei, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.

REFERENCES

1. Berek JS, Kehoe ST, Kumar L, Friedlander M. Cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2018; 143Suppl 259–78
2. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018; 68:284–96
3. Cheng M, Lee HH, Chang WH, Lee NR, Huang HY, Chen YJ, et al. Weekly dose-dense paclitaxel and triweekly low-dose cisplatin: a well-tolerated and effective chemotherapeutic regimen for first-line treatment of advanced ovarian, fallopian tube, and primary peritoneal cancer. Int J Environ Res Public Health. 2019; 16:E4794
4. Lee WL, Wang PH. Aberrant sialylation in ovarian cancers. J Chin Med Assoc. 2020; 83:337–44
5. Koo MM, Swann R, McPhail S, Abel GA, Elliss-Brookes L, Rubin GP, et al. Presenting symptoms of cancer and stage at diagnosis: evidence from a cross-sectional, population-based study. Lancet Oncol. 2020; 21:73–9
6. Su MH, Cho SW, Kung YS, Lin JH, Lee WL, Wang PH. Update on the differential diagnosis of gynecologic organ-related diseases in women presenting with ascites. Taiwan J Obstet Gynecol. 2019; 58:587–91
7. Liu CH, Horng HC, Wang PH. A case of ovarian cancer present with acute respiratory distress: spontaneous rupture of diaphragm. Taiwan J Obstet Gynecol. 2019; 58:712–4
8. van der Burg ME, van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med. 1995; 332:629–34
9. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996; 334:1–6
10. Neijt JP, Engelholm SA, Tuxen MK, Sorensen PG, Hansen M, Sessa C, et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol. 2000; 18:3084–92
11. du Bois A, Lück HJ, Meier W, Adams HP, Möbus V, Costa S, et al.; Arbeitsgemeinschaft Gynäkologische Onkologie Ovarian Cancer Study GroupA randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003; 95:1320–9
12. Yang ST, Cheng M, Lee NR, Chang WH, Lee YL, Wang PH. Paclitaxel-related nail toxicity. Taiwan J Obstet Gynecol. 2019; 58:709–11
13. Su MH, Chen GY, Lin JH, Lee HH, Chung KC, Wang PH. Paclitaxel-related dermatological problems: not only alopecia occurs. Taiwan J Obstet Gynecol. 2019; 58:877–9
14. Havrilesky LJ, Yang JC, Lee PS, Secord AA, Ehrisman JA, Davidson B, et al. Patient preferences for attributes of primary surgical debulking versus neoadjuvant chemotherapy for treatment of newly diagnosed ovarian cancer. Cancer. 2019; 125:4399–406
15. Coleridge SL, Bryant A, Lyons TJ, Goodall RJ, Kehoe S, Morrison J. Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer. Cochrane Database Syst Rev. 2019; 10:CD005343
16. Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al.; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials GroupNeoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010; 363:943–53
17. Wang PH. Neoadjuvant chemotherapy before definite operative approach for women with advanced-stage epithelial ovarian cancer. Taiwan J Obstet Gynecol. 2018; 57:623–4
18. Roze JF, Hoogendam JP, van de Wetering FT, Spijker R, Verleye L, Vlayen J, et al. Positron emission tomography (PET) and magnetic resonance imaging (MRI) for assessing tumour resectability in advanced epithelial ovarian/fallopian tube/primary peritoneal cancer. Cochrane Database Syst Rev. 2018; 10:CD012567
19. Alberts DS, Liu PY, Hannigan EV, O’Toole R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996; 335:1950–5
20. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al.; Gynecologic Oncology GroupIntraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006; 354:34–43
21. Clamp AR, James EC, McNeish IA, Dean A, Kim JW, O’Donnell DM, et al. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial. Lancet. 2019; 394:2084–95
22. van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen JH, Schreuder HWR, Hermans RHM, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018; 378:230–40
23. Munkley J, Scott E. Targeting aberrant sialylation to treat cancer. Medicines (Basel). 2019; 6:E102
24. Su KM, Wang PH, Yu MH, Chang CM, Chang CC. The recent progress and therapy in endometriosis-associated ovarian cancer. J Chin Med Assoc. 2020; 83:227–32
25. Daly J, Carlsten M, O’Dwyer M. Sugar free: novel immunotherapeutic approaches targeting siglecs and sialic acids to enhance natural killer cell cytotoxicity against cancer. Front Immunol. 2019; 10:1047
26. Mereiter S, Balmaña M, Campos D, Gomes J, Reis CA. Glycosylation in the era of cancer-targeted therapy: where are we heading? Cancer Cell. 2019; 36:6–16
27. Sung PL, Wen KC, Horng HC, Chang CM, Chen YJ, Lee WL, et al. The role of α2,3-linked sialylation on clear cell type epithelial ovarian cancer. Taiwan J Obstet Gynecol. 2018; 57:255–63
28. Rodrigues E, Schetters STT, van Kooyk Y. The tumour glycol-code as novel immune checkpoint for immunotherapy. Nature Rev Immunol. 2018; 18:204
29. Büll C, Boltje TJ, Balneger N, Weischer SM, Wassink M, van Gemst JJ, et al. Sialic acid blockade suppresses tumor growth by enhancing T cell-mediated tumor immunity. Cancer Res. 2018; 78:3574–88
30. Wen KC, Sung PL, Hsieh SL, Chou YT, Lee OK, Wu CW, et al. Α2,3-sialyltransferase type I regulates migration and peritoneal dissemination of ovarian cancer cells. Oncotarget. 2017; 8:29013–27
31. Xiao H, Woods EC, Vukojicic P, Bertozzi CR. Precision glycocalyx editing as a strategy for cancer immunotherapy. Proc Natl Acad Sci U S A. 2016; 113:10304–9
32. Cagnoni AJ, Pérez Sáez JM, Rabinovich GA, Mariño KV. Turning-off signaling by siglecs, selectins, and galectins: chemical inhibition of glycan-dependent interactions in cancer. Front Oncol. 2016; 6:109
33. Lee WC, Lee WL, Shyong WY, Yang LW, Ko MC, Yeh CC, et al. Altered ganglioside GD3 in HeLa cells might influence the cytotoxic abilities of NK cells. Taiwan J Obstet Gynecol. 2012; 51:199–205
34. Lee WC, Lee WL, Shyong WY, Yang LW, Ko MC, Sheu BC, et al. Increased concentration of sialidases by HeLa cells might influence the cytotoxic ability of NK cells. Taiwan J Obstet Gynecol. 2012; 51:192–8
35. Chang WW, Yu CY, Lin TW, Wang PH, Tsai YC. Soyasaponin I decreases the expression of alpha2,3-linked sialic acid on the cell surface and suppresses the metastatic potential of B16F10 melanoma cells. Biochem Biophys Res Commun. 2006; 341:614–9
36. Hsu CC, Lin TW, Chang WW, Wu CY, Lo WH, Wang PH, et al. Soyasaponin-I-modified invasive behavior of cancer by changing cell surface sialic acids. Gynecol Oncol. 2005; 96:415–22
37. Costello M, Fiedel BA, Gewurz H. Inhibition of platelet aggregation by native and desialised alpha-1 acid glycoprotein. Nature. 1979; 281:677–8
38. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al.; ICON7 InvestigatorsA phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011; 365:2484–96
39. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al.; Gynecologic Oncology GroupIncorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011; 365:2473–83
40. Tewari KS, Burger RA, Enserro D, Norquist BM, Swisher EM, Brady MF, et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. J Clin Oncol. 2019; 37:2317–28
41. Kusunoki S, Terao Y, Hirayama T, Fujino K, Ujihira T, Ota T, et al. Safety and efficacy of neoadjuvant chemotherapy with bevacizumab in advanced-stage peritoneal/ovarian cancer patients. Taiwan J Obstet Gynecol. 2018; 57:650–3
42. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366:2455–65
43. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366:2443–54
44. Grywalska E, Sobstyl M, Putowski L, Roliński J. Current possibilities of gynecologic cancer treatment with the use of immune checkpoint inhibitors. Int J Mol Sci. 2019; 20:E4705
45. González-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al.; PRIMA/ENGOT-OV26/GOG-3012 InvestigatorsNiraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019; 381:2391–402
46. Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019; 381:2403–15
47. Vergote I, Scambia G, O’Malley DM, Van Calster B, Park SY, Del Campo JM, et al.; TRINOVA-3/ENGOT-ov2/GOG-3001 investigatorsTrebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019; 20:862–76
48. Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018; 379:2495–505
49. Liu CH, Chang Y, Wang PH. Poly(ADP-ribose) polymerase (PARP) inhibitors and ovarian cancer. Taiwan J Obstet Gynecol. 2017; 56:713–4
50. Tavassoeli FA. World Health Organization classification of tumours: pathology and genetics of tumours of the breast and female genital organs. 2003LyonIARC press
51. Chang LC, Huang CF, Lai MS, Shen LJ, Wu FL, Cheng WF. Prognostic factors in epithelial ovarian cancer: a population-based study. PLoS One. 2018; 13:e0194993
52. Chiang YC, Chen CA, Chiang CJ, Hsu TH, Lin MC, You SL, et al. Trends in incidence and survival outcome of epithelial ovarian cancer: 30-year national population-based registry in taiwan. J Gynecol Oncol. 2013; 24:342–51
53. Chang WH, Wang KC, Lee WL, Huang N, Chou YJ, Feng RC, et al. Endometriosis and the subsequent risk of epithelial ovarian cancer. Taiwan J Obstet Gynecol. 2014; 53:530–5
54. Wang KC, Chang WH, Lee WL, Huang N, Huang HY, Yen MS, et al. An increased risk of epithelial ovarian cancer in Taiwanese women with a new surgico-pathological diagnosis of endometriosis. BMC Cancer. 2014; 14:831
55. Teng SW, Horng HC, Ho CH, Yen MS, Chao HT, Wang PH; Taiwan Association of Gynecology Systematic Review GroupWomen with endometriosis have higher comorbidities: analysis of domestic data in Taiwan. J Chin Med Assoc. 2016; 79:577–82
56. Lee WL, Chang WH, Wang KC, Guo CY, Chou YJ, Huang N, et al. The risk of epithelial ovarian cancer of women with endometriosis may be varied greatly if diagnostic criteria are different: a nationwide population-based cohort study. Medicine (Baltimore). 2015; 94:e1633
57. Bouberhan S, Shea M, Cannistra SA. Advanced epithelial ovarian cancer: do more options mean greater benefits? J Clin Oncol. 2019; 37:1359–64
58. Prat J, D’Angelo E, Espinosa I. Ovarian carcinomas: at least five different diseases with distinct histological features and molecular genetics. Hum Pathol. 2018; 80:11–27
59. Salazar C, Campbell IG, Gorringe KL. When is “type I” ovarian cancer not “type I”? Indications of an out-dated dichotomy. Front Oncol. 2018; 8:654
60. Cybulska P, Paula ADC, Tseng J, Leitao MM Jr, Bashashati A, Huntsman DG, et al. Molecular profiling and molecular classification of endometrioid ovarian carcinomas. Gynecol Oncol. 2019; 154:516–23
61. Mueller JJ, Schlappe BA, Kumar R, Olvera N, Dao F, Abu-Rustum N, et al. Massively parallel sequencing analysis of mucinous ovarian carcinomas: genomic profiling and differential diagnoses. Gynecol Oncol. 2018; 150:127–35
62. Chang CM, Yang YP, Chuang JH, Chuang CM, Lin TW, Wang PH, et al. Discovering the deregulated molecular functions involved in malignant transformation of endometriosis to endometriosis-associated ovarian carcinoma using a data-driven, function-based analysis. Int J Mol Sci. 2017; 18:E2345
63. Chang CM, Wang PH, Horng HC. Gene set-based analysis of mucinous ovarian carcinoma. Taiwan J Obstet Gynecol. 2017; 56:210–6
64. Chang CM, Chiou SH, Yang MJ, Yen MS, Wang PH. Gene set-based integrative analysis of ovarian clear cell carcinoma. Taiwan J Obstet Gynecol. 2016; 55:552–7
65. Sung PL, Wen KC, Chen YJ, Chao TC, Tsai YF, Tseng LM, et al. The frequency of cancer predisposition gene mutations in hereditary breast and ovarian cancer patients in taiwan: from BRCA1/2 to multi-gene panels. PLoS One. 2017; 12:e0185615
66. Chang CC, Wang ML, Lu KH, Yang YP, Juang CM, Wang PH, et al. Integrating the dysregulated inflammasome-based molecular functionome in the malignant transformation of endometriosis-associated ovarian carcinoma. Oncotarget. 2017; 9:3704–26
67. Chang CC, Su KM, Lu KH, Lin CK, Wang PH, Li HY, et al. Key immunological functions involved in the progression of epithelial ovarian serous carcinoma discovered by the gene ontology-based immunofunctionome analysis. Int J Mol Sci. 2018; 19:E3311
68. Chang CM, Chuang CM, Wang ML, Yang YP, Chuang JH, Yang MJ, et al. Gene set-based integrative analysis revealing two distinct functional regulation patterns in four common subtypes of epithelial ovarian cancer. Int J Mol Sci. 2016; 17:E1272
69. Oda K, Hamanishi J, Matsuo K, Hasegawa K. Genomics to immunotherapy of ovarian clear cell carcinoma: unique opportunities for management. Gynecol Oncol. 2018; 151:381–9
70. Nersesian S, Glazebrook H, Toulany J, Grantham SR, Boudreau JE. Naturally killing the silent killer: NK cell-based immunotherapy for ovarian cancer. Front Immunol. 2019; 10:1782
71. Cheng H, Wang Z, Fu L, Xu T. Macrophage polarization in the development and progression of ovarian cancers: an overview. Front Oncol. 2019; 9:421
72. Pawłowska A, Suszczyk D, Okła K, Barczyński B, Kotarski J, Wertel I. Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment. Clin Exp Immunol. 2019; 195:334–44
73. Lynam S, Lugade AA, Odunsi K. Immunotherapy for gynecologic cancer: current applications and future directions. Clin Obstet Gynecol. 2020; 63:48–63
74. Minetto P, Guolo F, Pesce S, Greppi M, Obino V, Ferretti E, et al. Harnessing NK cells for cancer treatment. Front Immunol. 2019; 10:2836
75. Rodriguez GM, Galpin KJC, McCloskey CW, Vanderhyden BC. The tumor microenvironment of epithelial ovarian cancer and its influence on response to immunotherapy. Cancers (Basel). 2018; 10:E242
76. Greppi M, Tabellini G, Patrizi O, Candiani S, Decensi A, Parolini S, et al. Strengthening the antitumor NK cell function for the treatment of ovarian cancer. Int J Mol Sci. 2019; 20:E890
77. Zhu H, Blum R, Bjordahl R, Gaidarova S, Rogers P, Lee TT, Abujarour R, et al. Pluripotent stem cell-derived NK cells with high-affinity non-cleavable CD16a mediate improved anti-tumor activity. Blood. 2020; 135:399–410
78. Mallmann-Gottschalk N, Sax Y, Kimmig R, Lang S, Brandau S. EGFR-specific tyrosine kinase inhibitor modifies NK cell-mediated antitumoral activity against ovarian cancer cells. Int J Mol Sci. 2019; 20:E4693
79. Wu J, Mishra HK, Walcheck B. Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy. J Leukoc Biol. 2019; 105:1297–303
80. Oyer JL, Gitto SB, Altomare DA, Copik AJ. PD-L1 blockade enhances anti-tumor efficacy of NK cells. Oncoimmunology. 2018; 7:e1509819
81. Felder M, Kapur A, Rakhmilevich AL, Qu X, Sondel PM, Gillies SD, et al. MUC16 suppresses human and murine innate immune responses. Gynecol Oncol. 2019; 152:618–28
82. Uppendahl LD, Felices M, Bendzick L, Ryan C, Kodal B, Hinderlie P, et al. Cytokine-induced memory-like natural killer cells have enhanced function, proliferation, and in vivo expansion against ovarian cancer cells. Gynecol Oncol. 2019; 153:149–57
83. Yeh CC, Horng HC, Wang PH. Recurrent miscarriage: are NK cell subsets a good predictor? J Chin Med Assoc. 2019; 82:443
84. Adib Rad H, Basirat Z, Mostafazadeh A, Faramarzi M, Bijani A, Nouri HR, et al. Evaluation of peripheral blood NK cell subsets and cytokines in unexplained recurrent miscarriage. J Chin Med Assoc. 2018; 81:1065–70
85. Adib Rad H, Basirat Z, Mostafazadeh A, Faramarzi M, Bijani A, Nouri HR, et al. Reply to: “recurrent miscarriage: are NK cell subsets a good predictor?”. J Chin Med Assoc. 2019; 82:444
86. Zhuang Y, Liu C, Liu J, Li G. Resistance mechanism of PD-1/PD-L1 blockade in the cancer-immunity cycle. Onco Targets Ther. 2020; 13:83–94
87. Yin M, Shen J, Yu S, Fei J, Zhu X, Zhao J, et al. Tumor-associated macrophages (TAMs): a critical activator in ovarian cancer metastasis. Onco Targets Ther. 2019; 12:8687–99
88. Liao LC, Hu B, Zhang SP. Macrophages participate in the immunosuppression of condyloma acuminatum through the PD-1/PD-L1 signaling pathway. J Chin Med Assoc. 2019; 82:413–8
89. Li YT, Lee WL, Wang PH. Immune response of condyloma acuminatum after 5-aminolevulinicacid-photodynamic therapy treatment. J Chin Med Assoc. 2019; 82:672
90. Liao LC, Hu B, Zhang SP. Reply to “immune response of condyloma acuminatum after 5-aminolevulinicacid-photodynamic therapy treatment”. J Chin Med Assoc. 2019; 82:673
91. Zhang Z, Li H, Zhao Z, Gao B, Meng L, Feng X. Mir-146b level and variants is associated with endometriosis related macrophages phenotype and plays a pivotal role in the endometriotic pain symptom. Taiwan J Obstet Gynecol. 2019; 58:401–8
92. Colvin EK. Tumor-associated macrophages contribute to tumor progression in ovarian cancer. Front Oncol. 2014; 4:137
93. Yafei Z, Jun G, Guolan G. Correlation between macrophage infiltration and prognosis of ovarian cancer-a preliminary study. Biomed Res. 2016; 27:305–12
94. Zhang M, He Y, Sun X, Li Q, Wang W, Zhao A, et al. A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J Ovarian Res. 2014; 7:19
95. Lan C, Huang X, Lin S, Huang H, Cai Q, Wan T, et al. Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer. Technol Cancer Res Treat. 2013; 12:259–67
96. Le Page C, Marineau A, Bonza PK, Rahimi K, Cyr L, Labouba I, et al. BTN3A2 expression in epithelial ovarian cancer is associated with higher tumor infiltrating T cells and a better prognosis. PLoS One. 2012; 7:e38541
97. Yuan X, Zhang J, Li D, Mao Y, Mo F, Du W, et al. Prognostic significance of tumor-associated macrophages in ovarian cancer: a meta-analysis. Gynecol Oncol. 2017; 147:181–7
98. De Nola R, Menga A, Castegna A, Loizzi V, Ranieri G, Cicinelli E, et al. The crowded crosstalk between cancer cells and stromal microenvironment in gynecological malignancies: biological pathways and therapeutic implication. Int J Mol Sci. 2019; 20:E2401
99. Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 2013; 23:249–62
100. Pulaski HL, Spahlinger G, Silva IA, McLean K, Kueck AS, Reynolds RK, et al. Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer. J Transl Med. 2009; 7:49
101. Alizadeh D, Zhang L, Hwang J, Schluep T, Badie B. Tumor-associated macrophages are predominant carriers of cyclodextrin-based nanoparticles into gliomas. Nanomedicine. 2010; 6:382–90
102. Wanderley CW, Colón DF, Luiz JPM, Oliveira FF, Viacava PR, Leite CA, et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Cancer Res. 2018; 78:5891–900
103. Chao KC, Chang CC, Yen MS, Wang PH. Anti-tumor activity of histone deacetylase inhibitors and the effect on ATP-binding cassette in ovarian carcinoma cells. Eur J Gynaecol Oncol. 2010; 31:402–10
104. Stenzel AE, Abrams SI, Moysich KB. A call for epidemiological research on myeloid-derived suppressor cells in ovarian cancer: a review of the existing immunological evidence and suggestions for moving forward. Front Immunol. 2019; 10:1608
105. Trillo-Tinoco J, Sierra RA, Mohamed E, Cao Y, de Mingo-Pulido Á, Gilvary DL, et al. AMPK alpha-1 intrinsically regulates the function and differentiation of tumor myeloid-derived suppressor cells. Cancer Res. 2019; 79:5034–47
106. Salminen A, Kauppinen A, Kaarniranta K. AMPK activation inhibits the functions of myeloid-derived suppressor cells (MDSC): impact on cancer and aging. J Mol Med (Berl). 2019; 97:1049–64
107. Solito S, Pinton L, Mandruzzato S. In brief: myeloid-derived suppressor cells in cancer. J Pathol. 2017; 242:7–9
108. Pyzer AR, Cole L, Rosenblatt J, Avigan DE. Myeloid-derived suppressor cells as effectors of immune suppression in cancer. Int J Cancer. 2016; 139:1915–26
109. Fleming V, Hu X, Weber R, Nagibin V, Groth C, Altevogt P, et al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front Immunol. 2018; 9:398
110. Groth C, Hu X, Weber R, Fleming V, Altevogt P, Utikal J, et al. Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. Br J Cancer. 2019; 120:16–25
111. Kamran N, Chandran M, Lowenstein PR, Castro MG. Immature myeloid cells in the tumor microenvironment: implications for immunotherapy. Clin Immunol. 2018; 189:34–42
112. Catalano S, Panza S, Augimeri G, Giordano C, Malivindi R, Gelsomino L, et al. Phosphodiesterase 5 (PDE5) is highly expressed in cancer-associated fibroblasts and enhances breast tumor progression. Cancers (Basel). 2019; 11:E1740
113. Ghisoni E, Imbimbo M, Zimmermann S, Valabrega G. Ovarian cancer immunotherapy: turning up the heat. Int J Mol Sci. 2019; 20:E2927
114. Farolfi A, Gurioli G, Fugazzola P, Burgio SL, Casanova C, Ravaglia G, et al. Immune system and DNA repair defects in ovarian cancer: implications for locoregional approaches. Int J Mol Sci. 2019; 20:E2569
115. Wang PH, Huang BS, Horng HC, Yeh CC, Chen YJ. Wound healing. J Chin Med Assoc. 2018; 81:94–101
116. Horng HC, Chang WH, Yeh CC, Huang BS, Chang CP, Chen YJ, et al. Estrogen effects on wound healing. Int J Mol Sci. 2017; 18:E2325
117. Chen GY, Chang CP, Wang PH. Burn wound and therapeutic challenge. J Chin Med Assoc. 2019; 82:748–9
118. Scapini P, Cassatella MA. Social networking of human neutrophils within the immune system. Blood. 2014; 124:710–9
119. Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017; 168:670–91
120. Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 2018; 32:1267–84
121. Bartlett EK, Flynn JR, Panageas KS, Ferraro RA, Sta Cruz JM, Postow MA, et al. High neutrophil-to-lymphocyte ratio (NLR) is associated with treatment failure and death in patients who have melanoma treated with PD-1 inhibitor monotherapy. Cancer. 2020; 126:76–85
122. Palella E, Cimino R, Pullano SA, Fiorillo AS, Gulletta E, Brunetti A, et al. Laboratory parameters of hemostasis, adhesion molecules, and inflammation in type 2 diabetes mellitus: correlation with glycemic control. Int J Environ Res Public Health. 2020; 17:E300
123. Lee WL, Chan IS, Wang PH. Does a simple hematological examination predict the response and side effects in patients undergoing induction chemotherapy and/or neoadjuvant chemotherapy? J Chin Med Assoc. 2020; 83:107–8
124. Liu YH, Lin YS. Platelet-lymphocyte and neutrophil-lymphocyte ratios: predictive factors of response and toxicity for docetaxel-combined induction chemotherapy in advanced head and neck cancers. J Chin Med Assoc. 2019; 82:849–55
125. Tola EN. The association between in vitro fertilization outcome and the inflammatory markers of complete blood count among nonobese unexplained infertile couples. Taiwan J Obstet Gynecol. 2018; 57:289–94
126. Huang QT, Zhou L, Zeng WJ, Ma QQ, Wang W, Zhong M, et al. Prognostic significance of neutrophil-to-lymphocyte ratio in ovarian cancer: a systematic review and meta-analysis of observational studies. Cell Physiol Biochem. 2017; 41:2411–8
127. Huang CY, Yang YC, Wang KL, Chen TC, Chen JR, Weng CS, et al. Possible surrogate marker for an effective dose-dense chemotherapy in treating ovarian cancer. Taiwan J Obstet Gynecol. 2016; 55:405–9
128. Templeton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Ocaña A, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014; 106:dju124
129. Asher V, Lee J, Innamaa A, Bali A. Preoperative platelet lymphocyte ratio as an independent prognostic marker in ovarian cancer. Clin Transl Oncol. 2011; 13:499–503
130. Pinto MP, Balmaceda C, Bravo ML, Kato S, Villarroel A, Owen GI, et al. Patient inflammatory status and CD4+/CD8+ intraepithelial tumor lymphocyte infiltration are predictors of outcomes in high-grade serous ovarian cancer. Gynecol Oncol. 2018; 151:10–7
131. Schnell A, Bod L, Madi A, Kuchroo VK. The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity. Cell Res 2020;30:285-99
132. Comoli P, Chabannon C, Koehl U, Lanza F, Urbano-Ispizua A, Hudecek M, et al.; European Society for Blood and Marrow Transplantation, Cellular Therapy & Immunobiology Working Party – Solid Tumor Sub-committeeDevelopment of adaptive immune effector therapies in solid tumors. Ann Oncol. 2019; 30:1740–50
133. Anandappa AJ, Wu CJ, Ott PA. Directing traffic: how to effectively drive T cells into tumors. Cancer Discov. 2020; 10:185–97
134. Fritsche E, Volk HD, Reinke P, Abou-El-Enein M. Toward an optimized process for clinical manufacturing of CAR-Treg cell therapy [published online ahead of print January 22, 2020]. Trends Biotechnoldoi: 10.1016/j.tibtech.2019.12.009
135. Santoiemma PP, Powell DJ Jr. Tumor infiltrating lymphocytes in ovarian cancer. Cancer Biol Ther. 2015; 16:807–20
136. Bagley SJ, O’Rourke DM. Clinical investigation of CAR T cells for solid tumors: lessons learned and future directions. Pharmacol Ther. 2020; 205:107419
137. Patel AJ, Richter A, Drayson MT, Middleton GW. The role of B lymphocytes in the immuno-biology of non-small-cell lung cancer. Cancer Immunol Immunother. 2020; 69:325–42
138. Gupta P, Chen C, Chaluvally-Raghavan P, Pradeep S. B Cells as an immune-regulatory signature in ovarian cancer. Cancers (Basel). 2019; 11:E894
139. Wouters MCA, Nelson BH. Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer. Clin Cancer Res. 2018; 24:6125–35
140. Yang C, Lee H, Jove V, Deng J, Zhang W, Liu X, et al. Prognostic significance of B-cells and pSTAT3 in patients with ovarian cancer. PLoS One. 2013; 8:e54029
141. Dong HP, Elstrand MB, Holth A, Silins I, Berner A, Trope CG, et al. NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma. Am J Clin Pathol. 2006; 125:451–8
142. Lundgren S, Berntsson J, Nodin B, Micke P, Jirström K. Prognostic impact of tumour-associated B cells and plasma cells in epithelial ovarian cancer. J Ovarian Res. 2016; 9:21
143. Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ, Watson PH, et al. CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin Cancer Res. 2012; 18:3281–92
144. Milne K, Köbel M, Kalloger SE, Barnes RO, Gao D, Gilks CB, et al. Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS One. 2009; 4:e6412
145. Santoiemma PP, Reyes C, Wang LP, McLane MW, Feldman MD, Tanyi JL, et al. Systematic evaluation of multiple immune markers reveals prognostic factors in ovarian cancer. Gynecol Oncol. 2016; 143:120–7
146. Zhang AW, McPherson A, Milne K, Kroeger DR, Hamilton PT, Miranda A, et al. Interfaces of malignant and immunologic clonal dynamics in ovarian cancer. Cell. 2018; 173:1755.e22–69.e22
Keywords:

Female; Immune system; Immunotherapy

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