Lymphomas are malignancies of lymphocytes, which exhibit expansion of malignant cells in lymph nodes, bone marrow, and often other tissues and organs . 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.
COMPOSITION OF THE TUMOR MICROENVIRONMENT
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 . 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 .
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 . When co-cultured with cytotoxic CD8+ T cells, Treg cells significantly suppress their cytotoxic function, particularly the production of granzyme B and perforin . 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 . Aside from simply recruiting naturally occurring Treg cells, lymphoma cells are also able to induce FOXP3 in normal T cells, thereby promoting regulatory function .
Many of the intratumoral T cells, although not expressing FOXP3, express a phenotype compatible with T-cell exhaustion . 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 . 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 .
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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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.
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