Abstract IA02: Immune exhaustion and suppression in lymphoma
Authors: Ansell Stephen M. 
Published: December 2020

Abstract
The tumor microenvironment in lymphoproliferative disorders, including lymphoma, shows a prevalence of intratumoral T cells suggesting an effective immune response to malignant B cells. This supposes that antigen-presenting cells present tumor-associated peptides to the immune system, resulting in T cells that are primed to target the malignant clone. It is anticipated that activated T cells will target the malignant cells and eradicate the tumor. However, while T cells appear plentiful in the tumor microenvironment in B-cell lymphoma, they are not able to eradicate the malignancy. Rather, the T cells appear inhibited, either due to immune suppression or immune exhaustion, and the lymphoma steadily progresses. An effective antitumor response requires presentation of tumor antigens to T cells in the context of major histocompatibility complex (MHC) proteins. The cells then receive a second activating signal resulting in proliferation of the T cells, expansion of a tumor-specific T-cell clone, and generation of cytotoxic proteins that lyse the lymphoma cell. To control this process, however, inhibitory receptors are typically upregulated upon T-cell activation that allow the process to be suppressed. This prevents damage to healthy tissue from T cells that remain inappropriately activated for protracted periods of time. In lymphoid malignancies, however, malignant B cells commonly overexpress the ligands for PD-1, namely PD-L1 and PD-L2. This results in suppression of the activated T cells and prevents the malignant clone from being eradicated. This leads to a subsequent problem, in which effector T cells are restimulated by the persistent presence of malignant cells that expressed tumor antigens which they are targeting. This repeat stimulation results in activation-induced exhaustion and upregulation of additional receptors that make the cells susceptible to apoptosis. These receptors, including TIM3, TIGIT, and LAG3, are then expressed on T cells whose effector function is severely impaired. The effector T cells expressing TIM3 and LAG3 have very little ability to proliferate or generate cytokines. Additional mechanisms that inhibit T-cell activation are present in lymphoma and include cytokine- and cell-mediated suppression. Among cytokines that mediate T-cell suppression, TGF-β plays a pivotal role in regulating immune responses by inhibiting the proliferation and differentiation in both CD4+ and CD8+ T cells. In B-cell malignancies, both malignant B cells and intratumoral T cells can synthesize and secrete TGF-β, and TGF-β inhibits intratumoral T-cell proliferation, upregulates Foxp3 expression, and suppresses the development of TH1 and TH17 cells. Similarly, IL-10 also inhibits the proliferation, cytokine production, and migratory capacities of T cells. IL-10 downregulates expression of MHC class II as well as costimulatory molecules CD80 and CD86 on dendritic cells, resulting in suboptimal stimulation of T cells. Furthermore, IL-10-expressing dendritic cells promote T regulatory cell development. In B-cell NHL, it has been shown that serum IL-10 levels are elevated and correlate with a poor prognosis. IL-10 further affects monocytes by downregulating HLA-DR expression, and IL-10-induced CD14+HLA-DRlow/- monocytes inhibit T-cell activation and proliferation. In addition to regulatory cytokines, cell-mediated suppression plays a crucial role in T-cell suppression. Myeloid-derived suppressor cells (MDSCs) and CD4+ regulatory T cells are two major types of cells mediating T-cell suppression. In B-cell NHL, increased numbers of MDSCs may contribute to elevated absolute monocytosis at diagnosis that correlates with poor outcome in In DLBCL patients. Tumor-infiltrating MDSCs promote cross-tolerance in B-cell lymphoma by expanding or recruiting regulatory T cells, which supports tumor growth. Regulatory T cells also suppress immune function. In B-cell NHL, we have found that the frequency of regulatory T cells is increased in biopsy specimens. Regulatory T cells suppress proliferation and cytokine production of intratumoral CD4+ cells as well as granule secretion by CD8+ T cells, resulting in suppressed cytotoxicity of effector T cells. We found that both recruitment of naturally occurring regulatory T cells and induction of inducible regulatory T cells contribute to elevated frequency of these cells in the tumor microenvironment of B-cell NHL. Furthermore, malignant B cells play a role in the recruitment and induction of regulatory T cells as chemokine CCL22 secreted by lymphoma cells and CD70 expression by CD19+ lymphoma cells are involved in the process. All of these mechanisms that result in T-cell suppression and exhaustion prevent an effective antitumor immune response in lymphoma. Combination strategies that both activate T cells and prevent their inhibition and suppression are needed to rectify these issues.
Citation Format: Stephen M. Ansell. Immune exhaustion and suppression in lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA02.