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 . 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’) .
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▪▪].
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.
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).
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.
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 .
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 . 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 , 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  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.
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 . 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 , 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 . 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 . A study in CD137L deficient mice showed that these were more prone to develop germinal center-derived lymphomas, in particular FL . 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].
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 ). Further studies would need to elucidate how this delicate balance is achieved in certain malignancies.
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  and Fig. 1).
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 , 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 . Binding of PD-1 by its ligands has also been reported to induce apoptosis of T cells  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 .
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 .
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 .
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 . 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].
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.
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.
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.
Conflicts of interest
There are no conflicts of interest.
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
1. Swerdlow S, Campo E, Harris N, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th edn. Lyon: IARC Press; 2008.
2. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 2005; 5:251–262.
3. Carbone A, Gloghini A, Kwong Y-L, et al. Diffuse large B cell lymphoma: using pathologic and molecular biomarkers
to define subgroups for novel therapy. Ann Hematol 2014; 93:1263–1277.
4. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8:22–33.
5. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol 2012; 30:429–457.
6. Hanahan D, Weinberg Ra. Hallmarks of cancer: the next generation. Cell 2011; 144:646–674.
7▪▪. Scott DW, Gascoyne RD. The tumour microenvironment
in B cell lymphomas. Nat Rev Cancer 2014; 14:517–534.
This is an elegant and comprehensive article on microenvironmental composition and intercellular crosstalk in malignant B cell lymphomas.
8▪▪. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013; 39:1–10.
This article nicely illustrates the physiological regulation of anticancer immunity and provides insights in mechanisms employed by tumor cells to evade immune surveillance.
9. Robbins PF, Lu Y-C, El-Gamil M, et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med 2013; 19:747–752.
10. Matsushita H, Vesely MD, Koboldt DC, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 2012; 482:400–404.
11. Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005; 5:263–274.
12. Khong HT, Restifo NP. Natural selection of tumor variants in the generation of ‘tumor escape’ phenotypes. Nat Immunol 2002; 3:999–1005.
13. Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol 2003; 21:807–839.
14. Wherry EJ. T cell exhaustion. Nat Immunol 2011; 131:492–499.
15▪. Speiser DE, Utzschneider DT, Oberle SG, et al. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? Nat Rev Immunol 2014; 14:768–774.
Excellent article on the role of T cell differentiation and adaption in chronic inflammatory processes and cancer.
16▪. Pasqualucci L, Khiabanian H, Fangazio M, et al. Genetics of follicular lymphoma transformation. Cell Rep 2014; 6:130–140.
This article deciphers the molecular mechanisms underlying tumor evolution in follicular lymphoma using next-generation sequencing techniques.
17. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 2011; 43:830–837.
18. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone modifying genes in non-Hodgkin lymphoma. Nature 2011; 476:298–303.
19. Morin RD, Mungall K, Pleasance E, et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood 2013; 122:1256–1265.
20. Schmitz R, Young RM, Ceribelli M, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics
. Nature 2012; 490:116–120.
21▪▪. Green MR, Kihira S, Liu CL, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci U S A 2015; 112:E1116–E1125.
To our knowledge this is the first report linking CREBBP mutations to altered MHC class II expression and pertubated composition of the tumor microenvironment in follicular lymphoma.
22. Beà S, Valdés-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci U S A 2013; 110:18250–18255.
23▪▪. Reichel J, Chadburn A, Rubinstein PG, et al. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood 2014; 125:1061–1072.
This study is the first to report on WES data in isolated HRS cells of cHL leading to the discovery of B2M mutations as being recurrent in the nodular sclerosis subtype of cHL.
24. Lohr JG, Stojanov P, Lawrence MS, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A 2012; 109:3879–3884.
25. De Miranda NFCC, Georgiou K, Chen L, et al. Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients. Blood 2014; 124:2544–2553.
26. Challa-Malladi M, Lieu YK, Califano O, et al. Combined genetic inactivation of β2-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 2011; 20:728–740.
27. Scholtysik R, Kreuz M, Hummel M, et al. Characterization of genomic imbalances in diffuse large B-cell lymphoma by detailed SNP-chip analysis. Int J Cancer 2015; 136:1033–1042.
28. Riemersma SA, Jordanova ES, Schop RF, et al. Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites. Blood 2000; 96:3569–3577.
29. Jordanova ES, Riemersma SA, Philippo K, et al. Hemizygous deletions in the HLA region account for loss of heterozygosity in the majority of diffuse large B-cell lymphomas of the testis and the central nervous system. Genes Chromosomes Cancer 2002; 35:38–48.
30▪. Twa DDW, Mottok A, Chan FC, et al. Recurrent genomic rearrangements in primary testicular lymphoma. J Pathol 2015; [Epub ahead of print].
This study uses a bacterial artifical chromosome capture technique to investigate genomic rearrangements in primary testicular DLBCL. Furthermore, this article provides evidence for CIITA being recurrently rearranged in this lymphoma subtype.
31▪. Okosun J, Bodor C, Wang J, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 2014; 46:176–181.
Another important study on the genetic mechanisms of transformation in follicular lymphoma.
32. Schatz JH, Horwitz SM, Teruya-Feldstein J, et al. Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis. Leukemia 2015; 29:237–241.
33. Khodabakhshi A, Morin RD, Fejes AP, et al. Recurrent targets of aberrant somatic hypermutation in lymphoma. Oncotarget 2012; 3:1308–1319.
34. Odejide O, Weigert O, Lane AA, et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 2013; 123:1293–1296.
35. Martinez N, Almaraz C, Vaque JP, et al. Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation. Leukemia 2014; 28:1334–1340.
36. Müschen M, Re D, Bräuninger A, et al. Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells. Cancer Res 2000; 60:5640–5643.
37. Maggio EM, van den Berg A, de Jong D, et al. Low frequency of FAS mutations in Reed-Sternberg cells of Hodgkin's lymphoma. Am J Pathol 2003; 162:29–35.
38. Takahashi H, Feuerhake F, Kutok JL, et al. FAS death domain deletions and cellular FADD-like interleukin 1β converting enzyme inhibitory protein (long) overexpression: alternative mechanisms for deregulating the extrinsic apoptotic pathway in diffuse large B-cell lymphoma subtypes. Clin Cancer Res 2006; 12:3265–3271.
39. Scholtysik R, Nagel I, Kreuz M, et al. Recurrent deletions of the TNFSF7 and TNFSF9 genes in 19p13.3 in diffuse large B-cell and Burkitt lymphomas. Int J Cancer 2012; 131:E830–E835.
40. Bertrand P, Maingonnat C, Penther D, et al. The costimulatory molecule CD70 is regulated by distinct molecular mechanisms and is associated with overall survival in diffuse large B-cell lymphoma. Genes Chromosomes Cancer 2013; 52:764–774.
41. Launay E, Pangault C, Bertrand P, et al. High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis. Leukemia 2012; 26:559–562.
42. Cheung K-JJ, Johnson Na, Affleck JG, et al. Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis. Cancer Res 2010; 70:9166–9174.
43▪▪. Twa DDW, Chan FC, Ben-Neriah S, et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 2014; 123:2062–2065.
This is the first study reporting on structural genomic alterations involving the programmed-death receptor ligands in various B cell lymphoma entities.
44. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010; 116:3268–3277.
45. Mottok A, Renné C, Seifert M, et al. Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities. Blood 2009; 114:4503–4506.
46. Weniger MA, Melzner I, Menz CK, et al. Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene 2006; 25:2679–2684.
47. Melzner I, Bucur AJ, Bruderlein S, et al. Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 2005; 105:2535–2542.
48▪▪. Gunawardana J, Chan FC, Telenius A, et al. Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nat Genet 2014; 46:329–335.
An important study highlighting a different mechanism causing aberrant activation of the JAK-STAT signaling pathway.
49. Ritz O, Guiter C, Castellano F, et al. Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma. Blood 2009; 114:1236–1242.
50. Rossi D, Trifonov V, Fangazio M, et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med 2012; 209:1537–1551.
51. Lenz G, Davis RE, Ngo VN, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 2008; 319:1676–1679.
52. Yan Q, Huang Y, Watkins AJ, et al. BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas. Haematologica 2012; 97:595–598.
53. Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes cause deregulation of NF-kB in diffuse large B-cell lymphoma. Nature 2009; 459:717–721.
54. Trøen G, Warsame A, Delabie J. CD79B and MYD88 mutations in splenic marginal zone lymphoma. ISRN Oncol 2013; 2013:252318.
55. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011; 470:115–119.
56. Schmitz R, Hansmann M-L, Bohle V, et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 2009; 206:981–989.
57. Kato M, Sanada M, Kato I, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 2009; 459:712–716.
58. Novak U, Rinaldi A, Kwee I, et al. The NF-κB negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas. Blood 2009; 113:4918–4921.
59. Seliger B. Molecular mechanisms of MHC class I abnormalities and APM components in human tumors. Cancer Immunol Immunother 2008; 57:1719–1726.
60. Garrido F, Algarra I, García-Lora A. The escape of cancer from T lymphocytes: immunoselection of MHC class I loss variants harboring structural-irreversible ‘hard’ lesions. Cancer Immunol Immunother 2010; 59:1601–1606.
61▪. Vijai J, Wang Z, Berndt SI, et al. A genome-wide association study of marginal zone lymphoma shows association to the HLA region. Nat Commun 2015; 6:5751.
Large scale GWAS study revealing a strong association with HLA susceptibility loci in malignant lymphomas.
62. Conde L, Halperin E, Akers NK, et al. Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32. Nat Genet 2010; 42:661–664.
63▪. Cerhan JR, Berndt SI, Vijai J, et al. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat Genet 2014; 46:1233–1238.
Large scale GWAS study revealing a strong association with HLA susceptibility loci in malignant lymphomas.
64. Enciso-Mora V, Broderick P, Ma Y, et al. A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24 21 and 10p14 (GATA3). Nat Genet 2010; 42:1126–1130.
65. Cresswell P, Turner MJ, Strominger JL. Papain-solubilized HL-A antigens from cultured human lymphocytes contain two peptide fragments. Proc Natl Acad Sci U S A 1973; 70:1603–1607.
66. Grey HM, Kubo RT, Colon SM, et al. The small subunit of hl-a antigens is β2-microglobulin. J Exp Med 1973; 138:1608–1612.
67. D’Urso CM, Wang ZG, Cao Y, et al. Lack of HLA class I antigen expression by cultured melanoma cells FO-1 due to a defect in B2m gene expression. J Clin Invest 1991; 87:284–292.
68. Edidin M, Achilles S, Zeff R, et al. Probing the stability of class I major histocompatibility complex (MHC) molecules on the surface of human cells. Immunogenetics 1997; 46:41–45.
69. Wang Z, Arienti F, Parmiani G, et al. Induction and functional characterization of β2-microglobulin (β2-μ)-free HLA class I heavy chains expressed by β2-μ-deficient human FO-1 melanoma cells. Eur J Immunol 1998; 28:2817–2826.
70. Maleno I, Aptsiauri N, Cabrera T, et al. Frequent loss of heterozygosity in the β2-microglobulin region of chromosome 15 in primary human tumors. Immunogenetics 2011; 63:65–71.
71. Kloor M, Michel S, Buckowitz B, et al. Beta2-microglobulin mutations in microsatellite unstable colorectal tumors. Int J Cancer 2007; 121:454–458.
72. Koopman LA, Corver WE, van der Slik AR, et al. Multiple genetic alterations cause frequent and heterogeneous human histocompatibility leukocyte antigen class I loss in cervical cancer. J Exp Med 2000; 191:961–976.
73. Chang C-C, Campoli M, Restifo NP, et al. Immune selection of hot-spot β2-microglobulin gene mutations, HLA-A2 allospecificity loss, and antigen-processing machinery component down-regulation in melanoma cells derived from recurrent metastases following immunotherapy. J Immunol 2005; 174:1462–1471.
74. Jordanova ES, Riemersma Sa, Philippo K, et al. Beta2-microglobulin aberrations in diffuse large B-cell lymphoma of the testis and the central nervous system. Int J Cancer 2003; 103:393–398.
75. Shaw S, Ginther Luce GE, Quinones R, et al. Two antigen-independent adhesion pathways used by human cytotoxic T-cell clones. Nature 1986; 323:262–264.
76. Petrányi GG, Pócsik E, Kotlán B, et al. Regulatory function of cell surface molecules CD2-, LFA- and β2-microglobulin in natural killer cell activity. Mol Immunol 1986; 23:1275–1279.
77. Karre K, Ljunggren HG, Piontek G, et al. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 1986; 319:675–678.
78▪. Liu Y, Abdul Razak FR, Terpstra M, et al. The mutational landscape of Hodgkin lymphoma cell lines determined by whole-exome sequencing. Leukemia 2014; 28:2248–2251.
This article provided the first evidence of the occurrence of B2M mutations in cHL.
79. Möller P, Herrmann B, Moldenhauer G, et al. Defective expression of MHC class I antigens is frequent in B-cell lymphomas of high-grade malignancy. Int J Cancer 1987; 40:32–39.
80. Riemersma SA, Oudejans JJ, Vonk MJ, et al. High numbers of tumour-infiltrating activated cytotoxic T lymphocytes, and frequent loss of HLA class I and II expression, are features of aggressive B cell lymphomas of the brain and testis. J Pathol 2005; 206:328–336.
81. Meissner TB, Liu Y-J, Lee K-H, et al. NLRC5 cooperates with the RFX transcription factor complex to induce MHC class I gene expression. J Immunol 2012; 188:4951–4958.
82. Neerincx A, Rodriguez GM, Steimle V, et al. NLRC5 controls basal MHC class I gene expression in an MHC enhanceosome-dependent manner. J Immunol 2012; 188:4940–4950.
83▪. Neerincx A, Jakobshagen K, Utermöhlen O, et al. The N-terminal domain of NLRC5 confers transcriptional activity for MHC class I and II gene expression. J Immunol 2014; 193:3090–3100.
This study describes and characterizes the functional domain of NLRC5 crucial for transcriptional regulation of MHC class I and II genes.
84. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002; 346:1937–1947.
85. Rimsza LM, Roberts Ra, Miller TP, et al. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular. Blood 2004; 103:4251–4258.
86. Roberts RA, Wright G, Rosenwald AR, et al. Loss of major histocompatibility class II gene and protein expression in primary mediastinal large B-cell lymphoma is highly coordinated and related to poor patient survival. Blood 2006; 108:311–318.
87. Diepstra A, van Imhoff GW, Karim-Kos HE, et al. HLA class II expression by Hodgkin Reed-Sternberg cells is an independent prognostic factor in classical Hodgkin's lymphoma. J Clin Oncol 2007; 25:3101–3108.
88. Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008; 359:2313–2323.
89. Riemersma SA, Jordanova ES, Haasnoot GW, et al. The relationship between HLA class II polymorphisms and somatic deletions in testicular B cell lymphomas of Dutch patients. Hum Immunol 2006; 67:303–310.
90. Booman M, Douwes J, Glas AM, et al. Mechanisms and effects of loss of human leukocyte antigen class II expression in immune-privileged site-associated B-cell lymphoma. Clin Cancer Res 2006; 12:2698–2705.
91. Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 2011; 471:377–381.
92▪. Loeffler M, Kreuz M, Haake A, et al. Genomic and epigenomic co-evolution in follicular lymphomas. Leukemia 2015; 29:456–463.
Another study investigating mechanisms of transformation in follicular lymphoma and potential targets of AID-mediated aberrant somatic hypermutation.
93. Masternak K, Muhlethaler-Mottet A, Villard J, et al. CIITA is a transcriptional coactivator that is recruited to MHC class II promoters by multiple synergistic interactions with an enhanceosome complex. Genes Dev 2000; 14:1156–1166.
94. Scholl T, Mahanta SK, Strominger JL. Specific complex formation between the type II bare lymphocyte syndrome-associated transactivators CIITA and RFX5. Proc Natl Acad Sci U S A 1997; 94:6330–6334.
95. Kretsovali A, Agalioti T, Spilianakis C, et al. Involvement of CREB binding protein in expression of major histocompatibility complex class II genes via interaction with the class II transactivator. Mol Cell Biol 1998; 18:6777–6783.
96. Fontes JD, Kanazawa S, Jean D, et al. Interactions between the class II transactivator and CREB binding protein increase transcription of major histocompatibility complex class II genes. Mol Cell Biol 1999; 19:941–947.
97▪. God JM, Cameron C, Figueroa J, et al. Elevation of c-MYC disrupts HLA class II–mediated immune recognition of human B cell tumors. J Immunol 2015.
In this article, the authors describe a mechanism how elevated levels of MYC lead to disruption of MHC class II mediated antigen presentation.
98. Guce AI, Mortimer SE, Yoon T, et al. HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism. Nat Struct Mol Biol 2013; 20:90–98.
99. Blum JS, Wearsch PA, Cresswell P. Pathways of Antigen Processing. Annu Rev Immunol 2013; 31:443–473.
100. O’Donnell PW, Haque A, Klemsz MJ, et al. Cutting edge: induction of the antigen-processing enzyme IFN-γ-inducible lysosomal thiol reductase in melanoma cells is STAT1-dependent but CIITA-independent. J Immunol 2004; 173:731–735.
101. Hastings KT. GILT: shaping the MHC class II-restricted peptidome and CD4+ T cell-mediated immunity. Front Immunol 2013; 4:429.
102. Hastings KT, Lackman RL, Cresswell P. Functional requirements for the lysosomal thiol reductase GILT in MHC class II-restricted antigen processing. J Immunol 2006; 177:8569–8577.
103. Phipps-Yonas H, Cui H, Sebastiao N, et al. Low GILT expression is associated with poor patient survival in diffuse large B-cell lymphoma. Front Immunol 2013; 4:425.
104. Pasero C, Barbarat B, Just-Landi S, et al. A role for HVEM, but not lymphotoxin-β receptor, in LIGHT-induced tumor cell death and chemokine production. Eur J Immunol 2009; 39:2502–2514.
105. Cai G, Freeman GJ. The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol Rev 2009; 229:244–258.
106. Gertner-Dardenne J, Fauriat C, Orlanducci F, et al. The co-receptor BTLA negatively regulates human Vγ9Vδ2 T-cell proliferation: a potential way of immune escape for lymphoma cells. Blood 2013; 122:922–931.
107. Corvaisier M, Moreau-Aubry A, Diez E, et al. Vγ9Vδ2 T cell response to colon carcinoma cells. J Immunol 2005; 175:5481–5488.
108. Bank I, Book M, Huszar M, et al. Vδ2+ γδ T lymphocytes are cytotoxic to the MCF 7 breast carcinoma cell line and can be detected among the T cells that infiltrate breast tumors. Clin Immunol Immunopathol 1993; 67:17–24.
109. D’Asaro M, La Mendola C, Di Liberto D, et al. Vγ9Vδ2 T lymphocytes efficiently recognize and kill zoledronate-sensitized, imatinib-sensitive, and imatinib-resistant chronic myelogenous leukemia cells. J Immunol 2010; 184:3260–3268.
110. Wilhelm M, Kunzmann V, Eckstein S, et al. γδ T cells for immune therapy of patients with lymphoid malignancies. Blood 2003; 102:200–206.
111. Cheung TC, Oborne LM, Steinberg MW, et al. T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment
. J Immunol 2009; 183:7286–7296.
112. Cheung TC, Steinberg MW, Oborne LM, et al. Unconventional ligand activation of herpesvirus entry mediator signals cell survival. Proc Natl Acad Sci U S A 2009; 106:6244–6249.
113. Bowman MR, Crimmins MA, Yetz-Aldape J, et al. The cloning of CD70 and its identification as the ligand for CD27. J Immunol 1994; 152:1756–1761.
114. Arens R, Tesselaar K, Baars PA, et al. Constitutive CD27/CD70 interaction induces expansion of effector-type T cells and results in IFNγ-mediated B cell depletion. Immunity 2001; 15:801–812.
115. Arens R, Schepers K, Nolte MA, et al. Tumor rejection induced by CD70-mediated quantitative and qualitative effects on effector CD8+ T cell formation. J Exp Med 2004; 199:1595–1605.
116. Arens R, Nolte MA, Tesselaar K, et al. Signaling through CD70 regulates B cell activation and IgG production. J Immunol 2004; 173:3901–3908.
117. Lens SMA, Drillenburg P, Den Drijver BFA, et al. Aberrant expression and reverse signalling of CD70 on malignant B cells. Br J Haematol 1999; 106:491–503.
118. Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 2004; 23:23–68.
119. Middendorp S, Xiao Y, Song J-Y, et al. Mice deficient for CD137 ligand are predisposed to develop germinal center-derived B-cell lymphoma. Blood 2009; 114:2280–2289.
120. Grønbæk K, Straten P thor, Ralfkiaer E, et al. Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity. Blood 1998; 92:3018–3024.
121. Peter ME, Hadji A, Murmann AE, et al. The role of CD95 and CD95 ligand in cancer. Cell Death Differ 2015; 22:549–559.
122. Baitsch L, Fuertes-Marraco SA, Legat A, et al. The three main stumbling blocks for anticancer T cells. Trends Immunol 2012; 33:364–372.
123. Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11:3887–3895.
124. Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009; 229:114–125.
125. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8:793–800.
126▪. Azoulay-Alfaguter I, Strazza M, Pedoeem A, et al. The coreceptor programmed death-1 inhibits T-cell adhesion by regulating Rap1. J Allergy Clin Immunol 2014; 1:5–8.
This study reveals details in how the PD-1/PD-L pathway regulates T cell adhesion.
127. Honda T, Egen JG, Lämmermann T, et al. Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity 2014; 40:235–247.
128. Egen JG, Rothfuchs AG, Feng CG, et al. Intravital imaging reveals limited antigen presentation and T cell effector function in mycobacterial granulomas. Immunity 2011; 34:807–819.
129. Egen JG, Rothfuchs AG, Feng CG, et al. Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas. Immunity 2008; 28:271–284.
130. Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009; 206:3015–3029.
131. Amarnath S, Mangus CW, Wang JCM, et al. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med 2011; 3:111ra120.
132. Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med 2003; 198:1875–1886.
133. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010; 11:889–896.
134. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2:261–268.
135. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the Pd-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192:1027–1034.
136. Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003; 33:2706–2716.
137. Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 2007; 8:239–245.
138. Schreiner B, Mitsdoerffer M, Kieseier BC, et al. Interferon-β enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J Neuroimmunol 2004; 155:172–182.
139. Rodig N, Ryan T, Allen JA, et al. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol 2003; 33:3117–3126.
140. Kinter AL, Godbout EJ, McNally JP, et al. The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008; 181:6738–6746.
141. Butte MJ, Keir ME, Phamduy TB, et al. PD-L1 interacts specifically with B7-1 to inhibit T cell proliferation. Immunity 2009; 27:111–122.
142. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res 2012; 18:1611–1618.
143▪. Shi M, Roemer MGM, Chapuy B, et al. Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. Am J Surg Pathol 2014; 38:1715–1723.
This study correlates structural alterations of PD-L2 with protein expression levels in-situ using immunohistochemistry.
144▪. Twa DDW, Steidl C. Structural genomic alterations in primary mediastinal large B-cell lymphoma. Leuk Lymphoma 2015; 21:1–12.
Comprehensive review on structural alterations and potential underlying mutational mechanisms in PMBCL.
145. Marzec M, Zhang Q, Goradia A, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A 2008; 105:20852–20857.
146. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9:798–809.
147. Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011; 19:456–469.
148. Karin M, Greten FR. NF-[kappa]B: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005; 5:749–759.
149. Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-kB as the matchmaker. Nat Immunol 2011; 12:715–723.
150▪▪. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014; 371:2189–2199.
An elegant and innovative study interrogating genomic alterations and response to immune checkpoint therapy in malignant melanoma.
151▪. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2014; 372:311–319.
First report on safety and efficacy of PD-1 blockade in patients with relapsed or refractory cHL.
152. Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol 2013; 31:4199–4206.
153. Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol 2014; 15:69–77.