Hide or defend, the two strategies of lymphoma immune evasion: potential implications for immunotherapy

Abstract

Evading immune eradication is a prerequisite for neoplastic progression and one of the hallmarks of cancer. Here, we review the different immune escape strategies of lymphoma and classify them into two main mechanisms. First, lymphoma cells may "hide" to become invisible to the immune system. This can be achieved by losing or downregulating MHC and/or molecules involved in antigen presentation (including antigen processing machinery and adhesion molecules), thereby preventing their recognition by the immune system. Second, lymphoma cells may "defend" themselves to become resistant to immune eradication. This can be achieved in several ways: by becoming resistant to apoptosis, by expressing inhibitory ligands that deactivate immune cells and/or by inducing an immunosuppressive (humoral and cellular) microenvironment. These immune escape mechanisms may have therapeutic implications. Their identification may be used to guide "personalized immunotherapy" for lymphoma.

Figure 1.

Lymphoma immune evasion mechanisms. (Top left panel) “Hide”. Tumor cells may become “invisible” to the immune system by down-regulating MHC, co-stimulatory (CD80 and CD86) and/or adhesion (CD54) molecules. Downregulation of CD58 allows tumor cells to escape killing by natural killer (NK) cells, which are activated by self-missing signal (loss of MHC-I). (Right panel) “Defend”. Tumor cells are seen by the immune system but avoid destruction through resistance to apoptosis signals and/or expression of inhibitory receptors. Tumor cells may resist apoptosis by different means: loss of FAS and/or TRAIL receptors (extrinsic pathway), hyperexpression of anti-apoptotic molecules such as BCL-2 (intrinsic pathway) or PI9 (Granzyme pathway). T cells can be inhibited by inhibitory ligands which are expressed by lymphoma cells or cells from their microenvironment such as PD-L1 or PD-L2/PD-1, LAG-3/MHC-II, CTLA-4/CD80 or CD86 and HLA-G/ILT. CD47 sends a “don’t eat me” signal to macrophages and DCs by interacting with its ligand SIRPa. Tumor cells may also express FAS-L to induce death of immune cells. Some molecules expressed by lymphoma cells may have dual roles: expression of MHC-II allows antigen presentation but also binds to the inhibitory receptor LAG-3; CD80 and CD86 stimulate T cells through CD28 but may also inhibit T cells through CTLA-4. (Bottom left panel) Immunosuppressive microenvironment. The tumor cells interact with their microenvironment to contribute to lymphoma immune evasion. IL-10 is a potent immunosuppressive cytokine that inhibits priming by dendritic cells (DC), promotes Th2 and Treg differentiation and M2 macrophages; TGF-β induces exhausted phenotype of CTL and Treg differentiation; IDO suppresses cytotoxic T lymphocyte (CTL) and NK immune response through degradation of tryptophan and production of kynurenine. Trp: tryptophan; Kyn: kynurenine; Gal: galectin; Ag: antigen.