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Genomic alterations underlying immune privilege in malignant lymphomas

Mottok, Anjaa,b; Steidl, Christiana,b

Current Opinion in Hematology: July 2015 - Volume 22 - Issue 4 - p 343–354
doi: 10.1097/MOH.0000000000000155
LYMPHOID BIOLOGY AND DISEASES: Edited by Ari M. Melnick
Free

Purpose of review Malignant lymphomas represent a remarkably heterogeneous group of cancers with respect to their oncogenome, phenotype and clinical presentation. Lymphoma cells benefit from limited immune surveillance and have developed various mechanisms to alter antitumor immune responses. This article summarizes our current knowledge about genomic alterations underlying acquired immune privilege in lymphoid cancers.

Recent findings The implementation and broad application of next-generation sequencing techniques have significantly expanded our knowledge about genetic alterations and perturbed cellular pathways underlying lymphomagenesis. Based on key discoveries in the past decade, the purview of subsequent studies expanded beyond the biology of the lymphoma cells to include the pathogenic contribution of immune cells, stromal components and associated crosstalk between malignant and nonmalignant cells in the tumor microenvironment. A number of genetic mechanisms have been described that elucidate how lymphoma cells are selected for evading immune recognition and reprogramming immune responses. These prominently include structural genomic changes of the CIITA and programmed death ligand (CD274/PDCD1LG2) loci, alterations affecting antigen presentation and mutations in JAK-STAT and NFκB signaling pathways.

Summary Further investigations will foster our understanding about synergy of immune escape mechanisms, and lay the foundation for the development of predictive biomarkers in the context of conceptually novel therapies targeting microenvironment-related biology, such as immunological checkpoint inhibition.

aCentre for Lymphoid Cancer, BC Cancer Agency

bDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada

Correspondence to Dr Christian Steidl, MD, Department of Lymphoid Cancer Research and Centre for Lymphoid Cancer, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada. E-mail: csteidl@bccancer.bc.ca

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INTRODUCTION

Malignant lymphomas arise from different cells of the immune system, and according to the current WHO classification more than 30 major subtypes are recognized, most of them stemming from B cells at different stages of development [1]. Current concepts emphasize acquisition of oncogenic genomic hits in a definite cell-of-origin context to give rise to the variable malignant phenotypes observed in B cell lymphomas [2,3]. For the majority of described genomic alterations, the anatomical and functional context of the germinal center reaction is critically needed for their occurrence and selection during lymphomagenesis [4,5].

Over the past decade, the focus in cancer research shifted noticeably from pathogenesis models centered solely on the description of accumulating genetic changes in malignant cells toward more comprehensive models considering the interactions between tumor cells and their microenvironment as important contributors to cancerogenesis. The significance of this cellular crosstalk led to the recognition of this aspect of tumor biology as an emerging hallmark of cancer (‘immune evasion’) and enabling characteristic (‘tumor promoting inflammation’) [6].

To date, microenvironment-related biology in lymphoid cancers has been primarily explored in a limited number of lymphoma entities with variable contribution of reactive immune cells in the microenvironment. These entities prominently include classical Hodgkin lymphoma (cHL), primary mediastinal large B cell lymphoma (PMBCL), mucosa-associated lymphoid tissue lymphoma and follicular lymphoma (FL) [7▪▪]. Among these, cHL represents the extreme example in a spectrum of diseases that feature a quantitatively dominant microenvironment composed of a multitude of different nonmalignant cell types from both the innate and adaptive immune system. In cHL, these ‘bystander’ cells are believed to be attracted by the malignant Hodgkin and Reed–Sternberg (HRS) cells as the master recruiters.

The tumor microenvironment and in particular its composition and spatial distribution can be perceived as a complex function of genetic alterations within the malignant cell population, the extent and dependence on the molecular crosstalk involving cytokines and chemokines and host-specific factors (e.g., antitumor inflammatory response or systemic immune competence). This results in three highly characteristic blueprints for the microenvironmental architecture of malignant lymphomas, termed ‘re-education’, ‘recruitment’ and ‘effacement’ [7▪▪]. The relevant aspects of the molecular crosstalk between malignant and nonmalignant cells were recently reviewed by Scott and Gascoyne [7▪▪], and prominently involve soluble mediators establishing the specific composition of the microenvironment and modulating antitumor immune responses.

In this article, we will draw attention to genetic alterations in malignant lymphoma cells that provide the somatic foundation for acquired immune privilege and evasion from immune surveillance. We will describe the recurrently mutated genes reported to date, outline the properties of the altered molecules in contrast to their physiological role and provide a rationale for therapeutic intervention to reestablish and/or reinitiate the ‘cancer immunity cycle’ [8▪▪].

Box 1

Box 1

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ANTITUMOR IMMUNITY

The immune system not only protects against infectious agents but also recognizes and eliminates autologous cells displaying nonself antigens or neoantigens which, in the case of malignant tumors, are often the result of cancer-specific genetic alterations [9,10]. T cell-dependent immune responses involve complex interactions between antigen-presenting cells (APCs) and T cells, which engage several stimulatory and inhibitory signaling molecules, and the entire process has to be strictly regulated to avoid misdirected and exuberant reactions that might lead to autoimmunity and excessive tissue damage.

This sophisticated apparatus has been exploited by cancer cells, and there is ample evidence that antitumor immunity is not a passively or randomly occurring process but rather an active, tumor-mediated event [11–13] that ultimately leads to reprogrammed and dysfunctional immune cells. Although some of these effects seem to be persistent, a proportion might be reversible and therapeutically targetable [14,15▪]. Importantly, effective targeting of this altered immune biology in the clinical setting will be accelerated by the identification of genomic and molecular alterations underlying immune privilege. Moreover, the integration of these findings with clinical and morphological parameters will help administering more tailored therapy to lymphoma patients.

The genomic aberrations discussed in this article can be broadly categorized according to the effect that they exert on the tumor microenvironment, such as (1) loss or downregulation of (surface) molecules leading to decreased immunogenicity of tumor cells, (2) increased expression of surface molecules suppressing immune cell function and (3) recruitment or induction of a regulatory cellular milieu.

A comprehensive list of genomic aberrations underlying acquired immune privilege is presented in Table 1.

Table 1

Table 1

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LOSS OR DOWNREGULATION OF (SURFACE) MOLECULES

Specific T cell subsets, defined by functional properties and phenotypes, play an important role in anticancer immunity. It is well established that to fulfill these functions, T lymphocytes need two distinct signals to become fully activated, antigen-dependent stimulation through the T cell receptor (TCR) and antigen-independent costimulatory or coinhibitory signaling. For the former, TCR stimulation is dependent on antigen presentation in conjunction with major histocompatibility complexes (MHC) on APCs including malignant B cells (Fig. 1).

FIGURE 1

FIGURE 1

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Major histocompatibility complex class I deficiency

Abnormalities of MHC class I expression represent one of the most frequent changes across different tumor types allowing the tumor cells to avoid destruction by cytotoxic CD8+ T cells (CTLs) [59,60]. Of importance, the human leukocyte antigen (HLA) locus on the short arm of chromosome 6 is a very common susceptibility locus for the development of a variety of lymphomas as identified by genome-wide association studies [61▪,62,63▪,64].

The MHC class I complex is composed of a transmembrane glycopolypeptide heavy chain and the noncovalently bound β2-microglobulin (B2M) light chain [65,66]. The association with B2M is not only required for the assembly and stabilization of the entire complex but also for maintaining a functionally active conformation and the presentation of peptides derived from intracellularly degraded proteins [67–69]. Alterations of the B2M gene have been described across a variety of solid tumors and malignant lymphomas [70–74]. The mutational pattern with frequent occurrence of loss of the start codon, truncating mutations and deletions as well as biallelic alterations established B2M as an important tumor suppressor gene in diffuse large B cell lymphoma (DLBCL) [17,18,26] with a reported frequency of up to 29%. In contrast, mutations in FL, Burkitt lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma and marginal zone lymphoma were either absent or rarely detected [21▪▪,22,26].

A recent study investigating the genetic mechanisms underlying transformation of FL has further demonstrated that B2M mutations are enriched in the transformed lymphomas with mutation patterns similar to the one observed in de-novo DLBCL, providing evidence for the existence of immune selection pressure during evolution to a high-grade malignancy [16▪]. Interestingly, mutations of CD58, a member of the immunoglobulin superfamily and ligand for the CD2 receptor on natural killer (NK) cells [75,76], have been found to co-occur frequently with B2M aberrations in de-novo DLBCL as well as in transformed FL (tFL), suggesting that B2M and CD58 mutations represent complementary mechanisms to establish immune privilege [16▪,26]. Specifically, the co-occurrence was attributed to the potentially synergistic effects of reduced recognition by cytotoxic T cells and inactivating NK cells, since it has been described in earlier studies that escape from CTLs triggers NK cell recognition as part of a compensation mechanism [26,77].

Reichel et al.[23▪▪] recently reported on whole-exome sequencing (WES) data obtained from HRS cells isolated using a flow cytometry-based cell sorting strategy. B2M was the most prevalent mutated gene (70%) in their cohort of 10 primary cHL cases, supporting WES data from cHL-derived cell lines in which B2M mutations were also described [78▪]. Interestingly, this genetic alteration was associated with the nodular sclerosis subtype, a correlation further strengthened by immunohistochemical analyses on formalin-fixed, paraffin-embedded tissue demonstrating a significant enrichment of cases lacking B2M protein expression in nodular sclerosis-type cHL [23▪▪].

As B2M is indispensible for the assembly of the MHC class I complex, genomic alterations in B2M led to concomitant absence of surface HLA-A/B/C staining in mutated DLBCL and cHL cases [23▪▪,26], a discovery that might also, in part, explain the reduction of MHC class I expression reported in earlier studies [79,80].

Recently NOD-like receptor family CARD domain containing 5 (NLRC5) (class I transactivator), a new member of the nucleotide-binding domain, leucine-rich repeat protein family, was identified to be involved in the transcriptional control of MHC class I [81,82] with a potential role in regulating also MHC class II transcription [83▪]. So far NLRC5 alterations have been rarely described in malignant lymphomas [18–20,27], and further analyses in conjunction with functional validations are warranted to establish a potential link to immune escape.

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Major histocompatibility complex class II deficiency

In their capacity as potent antigen-presenters, B cells normally express MHC class II molecules on their surface interacting with CD4+ T-helper cells. The loss of MHC class II has been previously linked to impaired survival in DLBCL, PMBCL and cHL [84–87]. However, in DLBCL, this survival disadvantage in patients with decreased MHC class II expression might be overcome by the addition of rituximab [88].

Several mechanisms have been described how malignant B cells are able to downregulate MHC molecules (Table 1). Homozygous and heterozygous deletions of the MHC class I and II locus on chromosome 6p occur frequently in DLBCL, with a predilection for those arising in ‘immune-privileged’ sites of the testes or brain [28,29,89,90].

Our group has described that in PMBCL and cHL structural genomic alterations of class II transactivator (CIITA), the master regulator of MHC class II transcription, are recurrent and likely causative of MHC class II loss [91]. Specifically, unbalanced chromosomal rearrangements and additional mutational events in the coding sequence and intron 1 of CIITA are frequently detectable in PMBCL tumor samples (unpublished observations). CIITA mutations have also been described in DLBCL [17,18,25] and concomitant with B2M mutations in tFL, indicating that CIITA and B2M mutations might act synergistically to impair both MHC class I and II expression [16▪]. Similar to what we and others have observed, CIITA likely represents a target of AID-mediated aberrant somatic hypermutation, again emphasizing the important role of the germinal center reaction for the acquisition of mutations in non-Ig genes relevant in lymphomagenesis [31▪,33,92▪]. However, the structural genomic aberrations appear to be a unique feature of PMBCL, cHL and DLBCL arising in immune-privileged sites of the body [30▪,91].

Interestingly, these rearrangements seem to be double-hit type alterations since CIITA-involving translocations not only lead to MHC class II downregulation, but also to overexpression of rearrangement partners, among which the ligands of the programmed death 1 (PD-1) receptor PD-L1 and PD-L2 are so far the most prevalently reported [43▪▪,91]. In our cohort of PMBCL samples, we found that 71% of CIITA break-apart positive cases also harbored structural genomic alterations of the PD-1 ligand loci (gain/amplification and/or translocation). The functional consequences of PD-1 ligand overexpression are described in the section ‘The PD-1/PD-L axis’.

It is well established that CIITA exerts its function on the MHC class II promoter in a multiprotein complex [93,94] involving RFX, X2BP and NF-Y, and that it can be modulated by other cofactors including CREB binding protein (CREBBP) [95,96], which interacts with the acidic domain of CIITA. Since histone modifiers have been shown to be frequently mutated in malignant lymphomas [17,18], it follows that CREBBP mutations may contribute to the immune evasion phenotype. Green et al.[21▪▪] provided the first evidence that FL tumors that harbor CREBBP mutations exhibit lower MHC class II transcript and protein levels. In addition, these changes seem to effect T cell proliferation and abundance of certain T cell subsets. However, further (functional) studies are needed to provide proof and a possible linkage to genomic alterations occurring in CIITA.

God et al.[97▪] investigated the low immunogenicity of tumors with high expression of v-myc avian myelocytomatosis viral oncogene homolog (MYC) and demonstrated that Burkitt lymphoma, characterized by hallmark translocations involving MYC, had low expression of HLA-DM and gamma-interferon-inducible lysosomal thiol reductase (GILT). Whereas MYC seemed to have no effect on surface MHC class II expression, HLA-DM and GILT were significantly downregulated and MHC class II-mediated antigen presentation of B cell lymphoma cells to CD4+ T cells was impaired. HLA-DM is a nonclassical MHC class II molecule which is responsible for loading the MHC complex with peptides, a process that is antagonized by HLA-DO [98,99]. GILT is an interferon gamma (IFNγ) inducible endolysosomal reductase [100], relevant for (buried) protein epitopes that require disulfide bond reduction in order to be presented by MHC II [101,102]. Low expression of GILT has so far only been reported in DLBCL [103] in which it was associated with inferior survival. The underlying genetic alterations, beside the potential role for MYC in this context, still need to be uncovered.

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Loss of costimulatory molecules

TNFRSF14 mutations are frequent in FL, tFL and DLBCL and include a combination of truncating mutations, deletions and copy number neutral loss of heterozygosity [16▪]. The pattern of alterations suggests a potential role for TNFRSF14 as a tumor suppressor gene; however, the reported data on the prognostic value of these aberrations are controversial [41,42] and the exact mechanisms involved are, in large part, speculation [41,42,104]. TNFRSF14 [encoding for herpesvirus entry mediator (HVEM)] is a member of the tumor necrosis factor (TNF) receptor superfamily and signals to T cells in which the effect is largely dependent on the interacting molecules, lymphotoxin-alpha (LTA), LIGHT (TNFSF14), B and T lymphocyte attenuator (BTLA) and CD160, eliciting differential responses [105]. In the context of B cell lymphomas, TNFRSF14 mutations and/or reduction in expression might lead to altered costimulatory signaling in T cells present in the microenvironment. On the other hand, it has been shown that HVEM expressing tumor cells are able to interfere via BTLA with proliferation and differentiation of Vγ9Vδ2 T cells [106], a T cell subset involved in the immunological control of epithelial and hematological malignancies [107–110], pointing toward a coinhibitory role of HVEM in this context. Moreover, it has also been reported that HVEM and BTLA molecules can directly interact on the same cells [111,112], suggesting that some of the functional consequences of TNFRSF14 mutations might be related to signaling in the malignant B cells. Therefore, future studies will have to focus on deciphering the differential effects of specific mutations on the biology of the malignant cells and their role in the establishment of immune privilege.

CD70 (TNFSF7), a member of the TNF super-family, is a costimulatory molecule interacting with CD27 and thereby important for T cell mediated antitumor responses [113–115]. Several reports have described recurrent deletions of the chromosomal region and mutations that cluster in exons coding for the functionally relevant TNF-like domain [18,24,39,40]. Recently it has been shown that TNFSF7 is frequently mutated in Chinese DLBCL patients (22%), often resulting in the generation of a truncated protein [25]. Although this pattern of genetic alterations suggests a tumor suppressor role, it is also well established that CD70 holds oncogenic properties by mediating growth and prosurvival signals, and its overexpression was shown to be correlated with impaired survival in B cell malignancies [40,116,117]. A direct link and the impact of TNFSF7 alterations with regards to microenvironment biology and immune privilege are still controversial and need to be established.

CD137L (TNFSF9) in conjunction with its receptor TNFRSF9 (CD137) provides survival signals for activated CTLs and promotes their development into a memory subset [118]. A study in CD137L deficient mice showed that these were more prone to develop germinal center-derived lymphomas, in particular FL [119]. In humans, deletions have been reported in approximately 10–15% of DLBCL cases and, of interest, these deletions often also encompass TNFSF7, which is located just centromeric of TNFSF9[17,39].

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Evading FAS/FAS-L mediated apoptosis

CD95 (Fas cell surface death receptor/TNFRSF6) is well known for its ability to mediate apoptosis upon engagement with its natural ligand CD95L, which is expressed on activated CTL and NK cells. Although CD95 is still expressed in many cancers, its proapoptotic function might be altered due to mutations and deletions affecting the death-domain of the protein. Such recurrent genomic aberrations have been described in FL, DLBCL and cHL [36–38,120]. On the other hand it is increasingly recognized that CD95 is also involved in multiple pathways unrelated to apoptosis and can indeed have a tumor-promoting function (reviewed in [121]). Further studies would need to elucidate how this delicate balance is achieved in certain malignancies.

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INCREASED EXPRESSION OF SURFACE MOLECULES SUPPRESSING IMMUNE CELL FUNCTION

The second signal involved in T cell mediated immune responses is antigen-independent ligand–receptor interactions. These can be either costimulatory or coinhibitory and are required in order to direct and fine-tune the immune response. T cell inhibitory receptors are membrane proteins that, upon binding to their respective ligands, transmit inhibitory signals into the cell (reviewed in [122] and Fig. 1).

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The programmed death 1/PD-1 ligand axis

The PD-1/PD-1L pathway is crucial for restraining the immune effector function of T cells in response to continuous antigen stimulation. PD-1 (encoded by PDCD1), a monomeric transmembrane receptor protein of the Ig superfamily [123], mediates cell-intrinsic inhibition of T cell activation and proliferation through SHP-1/2 mediated suppression of phosphorylated proteins downstream of the TCR resulting in an anergic and exhausted T cell phenotype [124]. Binding of PD-1 by its ligands has also been reported to induce apoptosis of T cells [125] and, in addition, influences T cell adhesion by negative regulation of the small GTPase Rap1 [126▪] thereby increasing T cell motility, weakening T cell–APC contact and reducing T cell effector function [127–129]. Furthermore, it effects the development and functional properties of regulatory T cells [130–132], which, together with type 2-like mononuclear phagocytes or tumor-associated macrophages and myeloid-derived suppressor cells, are crucial factors that facilitate immune evasion [133].

The two major ligands for PD-1, PD-L1 (encoded by CD274) and PD-L2 (encoded by PDCD1LG2), display different expression patterns with PD-L2 being mainly restricted to cells of the immune system, whereas PD-L1 is widely expressed also in cells outside of the hematopoietic system upon induction by proinflammatory cytokines [134–137]. Expression of both ligands is inducible upon stimulation with IFNβ, IFNγ and some interleukins [138–140]. Further complexity is added by PD-L1 being able to bind to CD80 (B7-1) thereby inhibiting T cell function independent of PD-1 [141].

Amplification of the PD-L1/2 locus along with JAK2 on chromosome 9p24.1 is frequent in PMBCL, cHL and DLBCL arising in immune privilege sites and is associated with increased protein expression levels [44,142,143▪].

Recently our group described for the first time rearrangements involving the PD-1 ligands in 20% of PMBCL, 7% of primary testicular DLBCL and, to a much lesser extent, in primary central nervous system lymphoma [43▪▪]. These rearrangements, mainly encompassing translocations and intrachromosomal deletions, have been shown to entail distinct mechanisms of how they can deregulate the expression of PD-L1 and PD-L2. When involving the 5′ region of the genes, PD-1 ligand expression is placed under the influence of an active strong promoter, such as CIITA or IGH, a classical oncogenic event seen in various B cell lymphoma entities [30▪,43▪▪]. Other fusion partners like IGHV7-81 and NRG1, both translocated to the 3′ region of PD-L1/2, may result in the loss of miRNA binding sites or involve 3′ cis regulatory elements [43▪▪,144▪]. Interestingly, the underlying heterogeneity of structural genomic aberrations affecting the PD-L loci seems to translate into quantitative and qualitative expression changes as it has been shown that mRNA levels of PD-L2 were significantly higher in PMBCL cases with rearrangements in comparison to cases with copy number variations. In contrast, mRNA expression levels of PD-L1 were similar for PMBCL cases harboring either copy number gains, amplifications or translocations [43▪▪]. These observations together with protein expression studies [143▪] highlight the specific importance of PD-L2 in the pathogenesis of PMBCL. One could also reasonably argue that these quantitative expression differences might ultimately explain differential treatment response to novel therapies such as immune checkpoint inhibitors and therefore could serve as important biomarkers.

In addition to the described structural genomic alterations, the expression of PD-1 ligands can be deregulated via Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling and Epstein -Barr virus infection in cHL and PMBCL [44,142]. Moreover, oncogenic nucleophosmin–anaplastic lymphoma kinase fusions found in anaplastic large cell lymphoma (ALK+) have been reported to result in indirect upregulation of PD-1 ligand expression through STAT3 activation [145].

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RECRUITMENT OR INDUCTION OF A REGULATORY CELLULAR MILIEU

A characteristic feature of cancer development and progression is unchecked growth that results in the destruction of normal tissue architecture. Key mediators of this process are soluble growth factors and their receptors that provide proliferation and survival signals required for tumorigenesis [6]. Together with angiogenic factors and adhesion molecules those cytokines and chemokines are able to orchestrate the composition of the microenvironment and facilitate niche formation. In particular, this is reflected by the relatively high abundance of regulatory T cells, tumor-associated macrophages and myeloid-derived suppressor cells, all contributing to an immunosuppressive microenvironment. The acquisition of these tumor-permissive phenotypes is attributed to immune-regulatory cytokines such as interleukin (IL)-4, IL-10, IL-13, chemokine (C-C motif) ligand 17, chemokine (C-C motif) ligand 22 and transforming growth factor β, and also to the complex interaction between immune cells, enabling them to convert their phenotype and alter their functional role in antitumor immune response [7▪▪,11,14,15▪]. A number of somatic mutations have been described across the broad spectrum of B cell lymphoma entities that might modulate the microenvironment via constitutive activation of the JAK-STAT and NFκB signaling pathways. Both pathways are frequently deregulated by oncogenic mutations (i.e., MYD88, CARD11, CD79B and JAK2 copy number gain) and deleterious alterations of tumor suppressors (i.e., TNFAIP3, SOCS1 and PTPN1). The most common targeted pathway members are listed in Table 1. Although a direct link of these mutations to the composition of the microenvironment is largely absent in the literature, key endogenous promoters of inflammation, such as IL-6, IL1β and TNF-α have been shown to be regulated targets of the JAK-STAT and NFκB pathways [146–149].

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CONCLUSION

A variety of acquired genomic changes affecting different pathways can contribute to an immune escape phenotype in malignant lymphoma cells by effectively subverting the ability of T cells to target and eliminate tumor cells (Fig. 2). Furthermore, recent studies have suggested that acquisition of immune evasion strategies and the sustained tumor promoting inflammation facilitate tumor progression and niche formation.

FIGURE 2

FIGURE 2

Knowledge of immune escape mechanisms employed by the tumor cells and synergistic relationships between different pathways in conjunction with a thorough analysis of immunological features of the tumor microenvironment holds the promise to identify immunotherapeutic targets and enable the rapid development of new therapeutic strategies. The potential of determining the genetic basis for clinical response to immune checkpoint inhibitors has been recently demonstrated in patients with malignant melanoma [150▪▪]. Preliminary results from phase 1 and 2 clinical trials in lymphoma patients provide evidence for efficacy and safety [151▪,152,153], but more data are imperatively needed in order to develop reliable prognostic and predictive biomarkers, applicable in routine clinical practice and to select patients upfront who will benefit from these therapeutic approaches.

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Acknowledgements

None.

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Financial support and sponsorship

A.M. is supported by a postdoctoral fellowship award from the Mildred-Scheel-Cancer Foundation. This work is supported by funds from the Canadian Institutes of Health Research and a Terry Fox Research Institute team grant (1023) to C.S. C.S. is the recipient of a Career Investigator Scholarship award from the Michael Smith Foundation of Health Research.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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An important study highlighting a different mechanism causing aberrant activation of the JAK-STAT signaling pathway.

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    Large scale GWAS study revealing a strong association with HLA susceptibility loci in malignant lymphomas.

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    Another study investigating mechanisms of transformation in follicular lymphoma and potential targets of AID-mediated aberrant somatic hypermutation.

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    In this article, the authors describe a mechanism how elevated levels of MYC lead to disruption of MHC class II mediated antigen presentation.

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    This study correlates structural alterations of PD-L2 with protein expression levels in-situ using immunohistochemistry.

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    Comprehensive review on structural alterations and potential underlying mutational mechanisms in PMBCL.

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    An elegant and innovative study interrogating genomic alterations and response to immune checkpoint therapy in malignant melanoma.

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    First report on safety and efficacy of PD-1 blockade in patients with relapsed or refractory cHL.

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    Keywords:

    biomarkers; genomics; lymphomagenesis; major histocompatibility complexes class I and II; microenvironment; programmed death 1 ligands

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