Secondary Logo

Journal Logo


Targeting immune checkpoints in lymphoma

Ansell, Stephen M.

Author Information
Current Opinion in Hematology: July 2015 - Volume 22 - Issue 4 - p 337-342
doi: 10.1097/MOH.0000000000000158
  • Free



Lymphomas are malignancies of lymphocytes, which exhibit expansion of malignant cells in lymph nodes, bone marrow, and often other tissues and organs [1]. Although malignant cells typically predominate at sites of involvement by lymphoma, other cells are also present, typically forming a rich immune infiltrate consisting of T-lymphocytes, monocytes, and macrophages and other immune cells including natural killer cells and dendritic cells [2–4]. Although an effective antitumor immune response has been demonstrated in lymphoma, the presence of these other cells in the tumor microenvironment has not consistently been associated with an improved clinical outcome, and the immune system seems unable to eradicate the malignant process.

The present review will discuss the composition of the immune microenvironment in lymphoma and highlight the barriers to an effective immunological antitumor response. New targets for potentially restoring the compromised immune system have been identified, and this review will highlight recent clinical results with immune checkpoint inhibitors, and focus specifically on the recently reported clinical efficacy of programmed cell death-1 (PD-1) blockade.

Box 1
Box 1:
no caption available


Lymphomas are common lymphoid cancers in which malignant cells, arrested at different stages of differentiation, involve lymph nodes and occasionally other tissues. Much work has been done in recent years to describe the molecular mechanisms responsible for transformation of the malignant cells, but far less is known about the role of the normal immune cells located within the tumor microenvironment. Many of the intratumoral cells are T-lymphocytes, which appear to be more than simple residual elements of normal lymphoid tissue; rather they appear to have a specific role in that increased numbers of intratumoral T cells correlate with improved outcome in a variety of different lymphoma histologies [5–10]. Although some of the intratumoral T cells have a cytotoxic phenotype and appear to be effector cells, many of them are FOXP3 positive and have regulatory function that suppresses the immune response [11–15]. The intratumoral T-cell response, in fact, appears skewed toward increased numbers of regulatory T cells [16–18]. The exact role of regulatory T cells, however, is unknown. Although there is significant suppression of T-cell function by regulatory T cells, these cells may also play a role in suppressing the function of malignant B cells.

The lymphoma cells present in the tumor play a dominant role by reeducating the microenvironment and promoting the presence of other cells, including macrophages, follicular dendritic cells, and follicular T-helper cells [19–22,23▪,24–26]. In addition, the malignant cells attract immune cells to the microenvironment and may modify the function of immune cells through cytokines and chemokine signaling [12,27]. The recruitment of the microenvironment is particularly clear in classical Hodgkin lymphoma in which a very diverse milieu of cells from the immune system, and variable numbers of stromal cells and fibroblasts, are assembled in response to the malignant Reed–Sternberg cells [28–30]. T cells are particularly dominant in this microenvironment and include T-helper cells and T-regulatory cells. Secretion of a variant of chemokines also attracts a significant macrophage infiltration, which has been shown to be associated with a poorer outcome in Hodgkin lymphoma [31]. Cytokines including interleukin (IL)-8 and IL-6 help to support the immune microenvironment and are also associated with a poorer outcome in this disease [32,33].

Although lymphoma cells recruit cells to the tumor and influence their phenotype, immune cells and stromal cells present within the tumor in turn play an active role and provide signals to lymphoma cells, which promote malignant growth and survival. B-cell receptor signaling in response to stimuli in the microenvironment may well sustain the growth of various lymphomas and in fact promote lymphomas [34,35]. Furthermore, constitutive activation of this pathway has been shown to be important in a variety of B-cell lymphomas, including mantle cell lymphoma, lymphoplasmacytic lymphoma, small lymphocytic lymphoma, and the activated B-cell type of diffuse large B-cell lymphoma [36–38]. Similarly, activation of the toll-like receptor pathway caused by antigens and microbes present in the microenvironment has been shown to activate lymphoma cell growth [39,40]. Toll-like receptor signaling plays a role in subtypes of diffuse large B-cell lymphoma, splenic marginal zone lymphoma, and lymphoplasmacytic lymphoma, and mutations in the MyD88 pathway appear to be particularly important in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia [41–43]. Additional support is provided by immune cells to the malignant cells through the secretion of cytokines. Cytokines such as IL-4, IL-6, and IL-21 can all promote malignant cell growth [44,45]. Furthermore B-cell activating factors and a proliferation inducing ligand (APRIL) have also been shown to be produced by cells in the microenvironment and to promote malignant cell growth [46].

Immunological barriers to an effective immune response

Although T cells and other immune effector cells are present in significant numbers within the tumor microenvironment, these cells appear unable to elicit an effective antitumor immune response. A variety of different mechanisms are present, which result in a highly suppressive immune microenvironment. Studies done on the CD4 positive T-cell population present within the tumor microenvironment show that many of these cells express FOXP3, a marker of regulatory T (Treg) cells, and testing of the FOXP3 positive Treg cells show them to be significantly immunosuppressive [47,48]. When autologous Treg cells are co-cultured with other T cells, proliferation and cytokine production is significantly suppressed [13]. When co-cultured with cytotoxic CD8+ T cells, Treg cells significantly suppress their cytotoxic function, particularly the production of granzyme B and perforin [15]. Lymphoma cells have been shown to recruit Treg cells by producing CCL22 and lymphoma cells co-cultured with regulatory T cells have shown an ability to promote migration of Treg cells in response to their presence [13]. Aside from simply recruiting naturally occurring Treg cells, lymphoma cells are also able to induce FOXP3 in normal T cells, thereby promoting regulatory function [16].

Many of the intratumoral T cells, although not expressing FOXP3, express a phenotype compatible with T-cell exhaustion [49]. Intratumoral CD8+ and CD4+ cells in both B-cell lymphoma and Hodgkin lymphoma show increased expression of PD-1 and Tim-3, markers of T-cell exhaustion [50–52]. When intratumoral PD-1+ Tim-3+ T cells were evaluated for their ability to proliferate, these cells displayed a significant decreased proliferative capacity [49]. Their ability to produce cytokines when stimulated was significantly decreased. Cytokine signaling, including signaling through the JAK/STAT pathway, was significantly downregulated. Interestingly, this T-cell exhaustion phenotype may in part be because of stimulation by immunostimulatory cytokines. Data have suggested that cytokines such as IL-12 rather than promoting an efficient immune response may overtime, in fact, induce T-cell exhaustion [49].

A further immunological barrier to an effective antitumor response is the overexpression of a variety of immunosuppressive ligands in the tumor microenvironment. Lymphoma cells have been shown to express transforming growth factor beta (TGF-β) on the cell surface and TGF-β induces significant immunosuppression by promoting FOXP3 expression and T-regulatory function [53]. Furthermore, TGF-β also induces CD70 expression and CD70 positive T cells exhibit evidence of T-cell exhaustion [54▪]. CD70+ T cells commonly have high expression of PD-1 and Tim-3, and a decreased ability to proliferate and produce cytokines. Other immunosuppressive ligands include the expression of programmed death ligand-1 (PD-L1) and PD-L2 on the malignant cell [55–57]. This is particularly true in Hodgkin lymphoma, T-cell lymphoma and primary mediastinal large B-cell lymphoma. Upregulation of PD-L1 and PD-L2 in these diseases is secondary to the genetic translocation of CIITA and PD-L1 or PD-L2, resulting in significant overexpression of these immunosuppressive ligands on malignant cells. Furthermore, the incorporation of EBV into the genome results in upregulation of PD-1 and this is commonly seen in classical Hodgkin lymphoma [55]. These immunosuppressive ligands make it extremely difficult for cytotoxic T cells to effectively suppress the malignant clone.

Monocytes and macrophages may further contribute to suppression of the immune response and growth of malignant cells [58,59]. Biopsy specimens from a variety of different lymphomas have shown significant numbers of intratumoral monocytes. Tumor-associated macrophages identified by the expression of CD68 or CD163 have been associated with disease progression and with suppression of T-cell function because of expression of PD-L1 [58]. The macrophages are also responsible for the production of immunosuppressive cytokines and co-culture of intratumoral macrophages with malignant cells promotes their growth and survival. Increased numbers of tumor-associated macrophages have been associated with a poor survival in patients with Hodgkin lymphoma and other types of B-cell lymphoma [20,21,31].

The tumor microenvironment in most lymphomas has multiple mechanisms in place that promote immune suppression and antagonize an efficient immune response. Negative immunological regulators (checkpoints) of the immune system predominate and thereby present an opportunity for modulation for therapeutic benefit. Initial studies using antibodies to block CTLA4 signaling and promote T-cell activation demonstrated some clinical benefit, but more recent studies preventing T-cell suppression by blocking PD-L1 and PD-L2 interactions with PD-1 have resulted in very promising clinical responses, particularly in patients with Hodgkin lymphoma.

Immune checkpoints as a target for therapy in lymphoma

CTLA4 is expressed on T cells after activation and functions to downregulate T-cell activity through a variety of mechanisms including preventing costimulation by outcompeting CD28 for its ligand B7 and also by inducing T-cell cycle arrest [60–62]. CTLA4 has a significant role in maintaining normal immunological homeostasis as confirmed by findings that mice deficient in CLTA4 die from a fatal lymphoproliferative process. Blocking CTLA4 therefore promotes the persistence and activation of intratumoral T cells [63,64].

Similarly, PD-1 is a negative regulator of T-cell activity and limits the activity of T cells by interaction with its two ligands, PD-L1 and PD-L2 [65]. When PD-1 is engaged by one of these ligands, it inhibits kinase signaling that typically leads to T-cell activation, thereby suppressing T-cell function. Mice deficient in PD-1 have an immune phenotype distinct from mice deficient in CTLA4, as CTLA4 is believed to primarily regulate early T-cell activation and PD-1 is believed to inhibit T-cell effector activity in the effector phase [66]. The PD-1 pathway is important in the tumor microenvironment, particularly because PD-L1 is commonly expressed by malignant cells and interacts with PD-1 on T cells to suppress an effective antitumor immune response [55–57,67].

Current clinical results with immune checkpoint inhibitors

In lymphoma, an initial clinical trial tested the use of the anti-CTLA4 antibody ipilimumab in B-cell lymphoma [68]. The rational for this study was to block CTLA4 signaling to enhance T-cell responses. In the clinical trial, 18 patients were treated and two responses were noted – one patient had a durable complete remission and one patient had a partial response. Correlative studies in this trial confirmed that T-cell proliferation to recall antigens was increased in a significant proportion of patients, suggesting that the immune response was activated and enhanced. Additional clinical trials utilizing ipilimumab tested this drug in patients who has progressed after allogeneic stem cell transplant [69]. In a study of 29 patients with a variety of hematologic malignancies, responses were predominantly seen in patients with lymphoma. There were two complete responses in patients with Hodgkin lymphoma and a partial response in a patient with mantle cell lymphoma. Interestingly, ipilimumab did not induce or exacerbate clinical graft versus host disease in this study.

Subsequent clinical trials using antibodies to block PD-1 interactions with PD-L1 and PD-L2 have resulted in very encouraging results. An initial study using pidilizumab after autologous stem cell transplant in patients with diffuse large B-cell lymphoma showed that the agent had promising clinical activity [70]. Pidilizumab is an anti-PD-1-humanized IgG1 monoclonal antibody and in this trial 66 eligible patients were treated. The primary endpoint of the study was progression free survival at 16 months. The endpoint of the study was met; and in the subset of high risk patients who remained positive on PET scan after salvage chemotherapy, the progression free survival was 70%. Even in patients with measurable disease after stem cell transplant, responses were seen with an overall response rate after pidilizumab treatment of 51%. Pidilizumab was combined with rituximab in a subsequent study in patients with relapsed follicular lymphoma [71▪]. In a trial of 32 patients, the combination was well tolerated with promising clinical results. Of 29 evaluable patients, 19 patients (66%) achieved an objective response and complete responses were seen in 15 (52%) of the patients.

Recent data utilizing nivolumab, an antibody that also targets PD-1, were reported. These results showed dramatic response rates in patients with Hodgkin lymphoma [72▪▪]. In a subset analysis, 23 patients with relapsed or refractory Hodgkin lymphoma were studied and an overall response rate of 87% was seen with 17% of the patients having a complete response to treatment. The progression free survival at 24 months was 86% and all of the patients benefited from the treatment. Of note, an analysis of pretreatment tumor specimens in 10 patients showed copy number gains in PD-L1 and PD-L2 with increased expression of the ligands in all patients. Furthermore, positive staining for STAT3, indicative of activated JAK/STAT signaling, was also confirmed. These correlative studies confirmed the relevance of targeting PD-1 as a method to overcome immune suppression.

A further analysis of other histological subtypes treated in the same study showed promising results in follicular lymphoma and large cell lymphoma [73]. In patients with follicular lymphoma, an overall response rate of 40% was seen. Similarly, in patients with diffuse large B-cell lymphoma, a response rate of 36% was seen. Although these results were not as impressive as those seen in Hodgkin lymphoma, targeting PD-1 in most lymphomas remains an important treatment approach. Additional studies will be needed to explain the differences in clinical responses seen between the histological subtypes and to identify biomarkers that identify which patients are likely to respond to this treatment.

Pembrolizumab is another antibody, which targets interactions between PD-1 and its ligands. Recent data utilizing this agent in classical Hodgkin lymphoma after failure of standard therapy also demonstrated a very high response rate [74▪▪]. In a study of 15 patients with classical Hodgkin lymphoma treated with pembrolizumab, an overall response rate of 53% was reported; 20% of patients had a complete response and 33% had a partial remission. Responses to this treatment have also been durable. Similar to the results seen in nivolumab-treated patients, overexpression of PD-L1 in the tumor microenvironment was seen in the majority of patients studied.


Treatment with immune checkpoint inhibitors has promising clinical activity in lymphoma, particularly in patients with Hodgkin lymphoma. Dramatic responses are not seen in all histologies of lymphoma, however, with no objective responses seen for example in patients with multiple myeloma. Further research will clearly be needed to understand differences in the biology and efficacy of these agents. In the lymphoma subtypes in which these agents are highly active, the future will most likely include combinations of immune checkpoint inhibitors and studies using immune checkpoint inhibitors to optimize the immune responses induced by other immunological approaches. To test this, studies utilizing ipilimumab in combination with anti-PD-1 therapy are currently in progress, but other combinations will clearly need to be explored. Combinations with other agents, including antibody drug conjugates, small molecule inhibitors, and even chemotherapy, are also attractive. These studies will have to be carefully and rationally designed to avoid suppressing the very cells that immune checkpoint inhibition is activating. With thoughtful study design, integration of these effective agents into future combination approaches and future frontline therapy is anticipated.



Financial support and sponsorship


Conflicts of interest

S.A. has received research funding from Bristol-Myers Squibb, Seattle Genetics, and Celldex Therapeutics.


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

  • ▪ of special interest
  • ▪▪ of outstanding interest


1. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2008.
2. Yang ZZ, Ansell SM. The tumor microenvironment in follicular lymphoma. Clin Adv Hematol Oncol 2012; 10:810–818.
3. de Jong D, Fest T. The microenvironment in follicular lymphoma. Best Pract Res Clin Haematol 2011; 24:135–146.
4. Coupland SE. The challenge of the microenvironment in B-cell lymphomas. Histopathology 2011; 58:69–80.
5. de Jong D, Koster A, Hagenbeek A, et al. Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols. Haematologica 2009; 94:70–77.
6. Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 2004; 351:2159–2169.
7. Ansell SM, Stenson M, Habermann TM, et al. CD4+ T-cell immune response to large B-cell non-Hodgkin's lymphoma predicts patient outcome. J Clin Oncol 2001; 19:720–726.
8. Lee AM, Clear AJ, Calaminici M, et al. Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome. J Clin Oncol 2006; 24:5052–5059.
9. Wahlin BE, Sundstrom C, Holte H, et al. T cells in tumors and blood predict outcome in follicular lymphoma treated with rituximab. Clin Cancer Res 2011; 17:4136–4144.
10. Wahlin BE, Sander B, Christensson B, Kimby E. CD8+ T-cell content in diagnostic lymph nodes measured by flow cytometry is a predictor of survival in follicular lymphoma. Clin Cancer Res 2007; 13 (2 Pt 1):388–397.
11. Laurent C, Muller S, Do C, et al. Distribution, function, and prognostic value of cytotoxic T lymphocytes in follicular lymphoma: a 3-D tissue-imaging study. Blood 2011; 118:5371–5379.
12. Carreras J, Lopez-Guillermo A, Roncador G, et al. High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin Oncol 2009; 27:1470–1476.
13. Yang ZZ, Novak AJ, Stenson MJ, et al. Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood 2006; 107:3639–3646.
14. Hilchey SP, De A, Rimsza LM, et al. Follicular lymphoma intratumoral CD4+CD25+GITR+ regulatory T cells potently suppress CD3/CD28-costimulated autologous and allogeneic CD8+CD25 and CD4+CD25 T cells. J Immunol 2007; 178:4051–4061.
15. Yang ZZ, Novak AJ, Ziesmer SC, et al. Attenuation of CD8+ T-cell function by CD4+CD25+ regulatory T cells in B-cell non-Hodgkin's lymphoma. Cancer Res 2006; 66:10145–10152.
16. Yang ZZ, Novak AJ, Ziesmer SC, et al. CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. Blood 2007; 110:2537–2544.
17. Ai WZ, Hou JZ, Zeiser R, et al. Follicular lymphoma B cells induce the conversion of conventional CD4+ T cells to T-regulatory cells. Int J Cancer 2009; 124:239–244.
18. Yang ZZ, Novak AJ, Ziesmer SC, et al. Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin's lymphoma. Cancer Res 2009; 69:5522–5530.
19. Mittal S, Marshall NA, Duncan L, et al. Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma. Blood 2008; 111:5359–5370.
20. Farinha P, Masoudi H, Skinnider BF, et al. Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood 2005; 106:2169–2174.
21. Taskinen M, Karjalainen-Lindsberg ML, Nyman H, et al. A high tumor-associated macrophage content predicts favorable outcome in follicular lymphoma patients treated with rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone. Clin Cancer Res 2007; 13:5784–5789.
22. Lin Y, Gustafson MP, Bulur PA, et al. Immunosuppressive CD14+HLA-DR(low)/- monocytes in B-cell non-Hodgkin lymphoma. Blood 2011; 117:872–881.
23▪. Smeltzer JP, Jones JM, Ziesmer SC, et al. Pattern of CD14+ follicular dendritic cells and PD1+ T cells independently predicts time to transformation in follicular lymphoma. Clin Cancer Res 2014; 20:2862–2872.

Manuscript shows that increased numbers of exhausted T cells and follicular dendritic cells are associated with a shorter time to lymphoma transformation.

24. Ame-Thomas P, Le Priol J, Yssel H, et al. Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells. Leukemia 2012; 26:1053–1063.
25. Hilchey SP, Rosenberg AF, Hyrien O, et al. Follicular lymphoma tumor-infiltrating T-helper (T(H)) cells have the same polyfunctional potential as normal nodal T(H) cells despite skewed differentiation. Blood 2011; 118:3591–3602.
26. Pangault C, Ame-Thomas P, Ruminy P, et al. Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent T(FH)-B cell axis. Leukemia 2010; 24:2080–2089.
27. Jones EA, Pringle JH, Angel CA, Rees RC. Th1/Th2 cytokine expression and its relationship with tumor growth in B cell non-Hodgkin's lymphoma (NHL). Leuk Lymphoma 2002; 43:1313–1321.
28. Montes-Moreno S. Hodgkin's lymphomas: a tumor recognized by its microenvironment. Adv Hematol 2011; 2011:142395.
29. Steidl C, Connors JM, Gascoyne RD. Molecular pathogenesis of Hodgkin's lymphoma: increasing evidence of the importance of the microenvironment. J Clin Oncol 2011; 29:1812–1826.
30. Greaves P, Clear A, Owen A, et al. Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells. Blood 2013; 122:2856–2863.
31. Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med 2010; 362:875–885.
32. van den Berg A, Visser L, Poppema S. High expression of the CC chemokine TARC in Reed-Sternberg cells: a possible explanation for the characteristic T-cell infiltrate in Hodgkin's lymphoma. Am J Pathol 1999; 154:1685–1691.
33. Marri PR, Hodge LS, Maurer MJ, et al. Prognostic significance of pretreatment serum cytokines in classical Hodgkin lymphoma. Clin Cancer Res 2013; 19:6812–6819.
34. Niemann CU, Wiestner A. B-cell receptor signaling as a driver of lymphoma development and evolution. Semin Cancer Biol 2013; 23:410–421.
35. Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov 2013; 12:229–243.
36. Stevenson FK, Krysov S, Davies AJ, et al. B-cell receptor signaling in chronic lymphocytic leukemia. Blood 2011; 118:4313–4320.
37. Quiroga MP, Balakrishnan K, Kurtova AV, et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood 2009; 114:1029–1037.
38. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463:88–92.
39. Quinn ER, Chan CH, Hadlock KG, et al. The B-cell receptor of a hepatitis C virus (HCV)-associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis. Blood 2001; 98:3745–3749.
40. Hermine O, Lefrère F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002; 347:89–94.
41. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011; 470:115–119.
42. Harsini S, Beigy M, Akhavan-Sabbagh M, Rezaei N. Toll-like receptors in lymphoid malignancies: double-edged sword. Crit Rev Oncol Hematol 2014; 89:262–283.
43. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med 2012; 367:826–833.
44. Fabre-Guillevin E, Tabrizi R, Coulon V, et al. Aggressive non-Hodgkin's lymphoma: concomitant evaluation of interleukin-2, soluble interleukin-2 receptor, interleukin-4, interleukin-6, interleukin-10 and correlation with outcome. Leuk Lymphoma 2006; 47:603–611.
45. Charbonneau B, Maurer MJ, Ansell SM, et al. Pretreatment circulating serum cytokines associated with follicular and diffuse large B-cell lymphoma: a clinic-based case-control study. Cytokine 2012; 60:882–889.
46. Novak AJ, Grote DM, Stenson M, et al. Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome. Blood 2004; 104:2247–2253.
47. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4:330–336.
48. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299:1057–1061.
49. Yang ZZ, Grote DM, Ziesmer SC, et al. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J Clin Invest 2012; 122:1271–1282.
50. Jin HT, Anderson AC, Tan WG, et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A 2010; 107:14733–14738.
51. Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 2010; 207:2175–2186.
52. Sakuishi K, Apetoh L, Sullivan JM, et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore antitumor immunity. J Exp Med 2010; 207:2187–2194.
53. Yang ZZ, Grote DM, Ziesmer SC, et al. Soluble and membrane-bound TGF-β-mediated regulation of intratumoral T cell differentiation and function in B-cell non-Hodgkin lymphoma. PLoS One 2013; 8:e59456.
54▪. Yang ZZ, Grote DM, Xiu B, et al. TGF-β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma. Leukemia 2014; 28:1872–1884.

This article reports that immunostimulatory cytokines such as TGF-β may induce T-cell exhaustion with sustained signaling.

55. 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.
56. Wilcox RA, Feldman AL, Wada DA, et al. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood 2009; 114:2149–2158.
57. 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.
58. Wilcox RA, Wada DA, Ziesmer SC, et al. Monocytes promote tumor cell survival in T-cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells. Blood 2009; 114:2936–2944.
59. Wahlin BE, Aggarwal M, Montes-Moreno S, et al. A unifying microenvironment model in follicular lymphoma: outcome is predicted by programmed death-1-positive, regulatory, cytotoxic, and helper T cells and macrophages. Clin Cancer Res 2010; 16:637–650.
60. Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994; 1:405–413.
61. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995; 182:459–465.
62. Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol 2001; 1:220–228.
63. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271:1734–1736.
64. Shrikant P, Khoruts A, Mescher MF. CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism. Immunity 1999; 11:483–493.
65. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26:677–704.
66. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer-preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol 2010; 37:430–439.
67. Andorsky DJ, Yamada RE, Said J, et al. Programmed death ligand 1 is expressed by nonhodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res 2011; 17:4232–4244.
68. Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res 2009; 15:6446–6453.
69. Bashey A, Medina B, Corringham S, et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 2009; 113:1581–1588.
70. 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.
71▪. 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.

Report of a high response rate including high numbers of complete responses when follicular lymphoma patients received rituximab and PD-1 blockade.

72▪▪. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015; 372:311–319.

This manuscript reports a response rate of 87% in patients with relapsed and refractory Hodgkin lymphoma who received treatment with an anti-PD-1 antibody.

73. Lesokhin AM, Ansell SM, Armand P, et al. Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies. ASH Annual Meeting 2014; Abstract 291.
74▪▪. Moskowitz CH, Ribrag V, Michot JM, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). ASH Annual Meeting 2014; Abstract 290.

immune checkpoint inhibitors; lymphoma; programmed cell death-1; tumor microenvironment

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.