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. 2020 Dec 14;11:594841. doi: 10.3389/fimmu.2020.594841

Figure 4.

Figure 4

Immune escape through PD-1/PD-L1 pathway in B-cell malignancies. As opposed to solid cancers, the malignant B lymphoma cell is also an immune cell, and its tumor microenvironment contains highly variable numbers of immune cells. B-cell malignancies arise in lymphoid tissues, and more precisely germinal center of lymph nodes (82). Molecular dissection of the malignant B-cell allows to understand the progressive behavior of different B-cell lymphoma subtypes. Among genetic alterations contributing to immune escape is the 9p24.1 copy gain or amplification, described many times in inflammatory lymphomas such as HL or Primary Mediastinal B Lymphoma (84), and correlated with overexpression of PD-L1 and PD-L2 on the surface of malignant cells (85). Two other mechanisms responsible for the malignant B lymphocyte inability to present tumor antigen to the CD8+ or CD4+ TLs are, respectively, loss of function of the gene encoding the β2-microglobulin (MHC I complex dysfunction) (54, 86) and the dysfunction of CIITA (encoding MHC II) (87). PD-L1 is highly expressed on tumor-infiltrating macrophages and the surface of tumor cells and APCs in the tumor microenvironment (76). In a HL model, PD-L1+ macrophages were frequently in contact with PD-1 CD4+ TLs, suggesting that macrophages drive CD4+ TL dysfunction via PD-1/PD-L1 interactions, and/or by preventing direct access to Hodgkin Reed-Sternberg cells (88). Tumor cells upregulate PD-L1 to dampen cytotoxic TL attack. This upregulation is a consequence of pro-inflammatory cytokine production by tumor infiltrating immune cells: IFNγ is produced by CD4+ and CD8+ TLs and acts as a potent PD-L1 upregulator (76). In a CLL model, Beyer et al. observed a significantly increased expression of TGF-β and IL-10 in Tregs from patients. Both cytokines play an important role for the CD8+ TL inhibitory function of these cells (89). For example, in FL, malignant cells guide differentiation of CD4+ TLs, skewing the population within the tumor towards Tregs. APC, Antigen Presenting Cell; HL, Hodgkin Lymphoma; IFNγ, Interferon Gamma; IL-2, Interleukine 2; IL-10, Interleukine 10; MHC, Major Histocompatibility Complex; PD-1, Programmed Death 1; PD-L1, Programmed Death Ligand 1; PD-L2, Programmed Death Ligand 2; TAM, Tumor Associated Macrophage; TCR, T-cell Receptor; TGF-β, Transforming Growth Factor Beta; TIL, Tumor-infiltrating Lymphocyte; Treg, Regulatory T Lymphocyte.