Cross talk between tumor cells and their cellular microenvironment. According to lessons learned from classic Hodgkin lymphoma (cHL), expression of PD-L1 can be found in tumor B cells, and expression of PD-1 is found on microenvironmental T cells in lymphomas with an inflammatory/immune cell-rich microenvironment. PD-1, which acts as an immunomodulatory molecule, is a negative regulator of activated T cells, B cells, and myeloid cells. PD-L1, a ligand of PD-1, is expressed on T cells, B cells, dendritic cells, and macrophages. (A) PD-L1 binds to PD-1 on T cells and regulates their activity. Binding of PD-1 to T cells with PD-L1 and 2 to HRS cells43 inactivates tumor-specific T cells, functioning as a checkpoint used by HRS cells and other tumor B cells to escape immune surveillance and evade immune destruction. (B) Classic HL with PD-L1 upregulation, acquired in HRS cells through highly recurrent copy gains of the chromosomal region containing the PD-L1 locus, is sensitive to PD-1 blockade therapy.12,13,44-46 In cHL and other lymphomas with inflammatory/immune cell-rich microenvironment, PD-L1 might be expressed by tumor cells and TAMs. PD-L1 binds to PD-1 on CD4+ and CD8+ T cells, attenuating the function of T cells and inhibiting the release of cytokines, leading to the immune escape of tumor cells. Following an antilymphoma immune response, lymphoma cells may recruit numerous TAMs and acquire genetic alterations that affect antigen presentation to T cells and upregulate the expression of PD-L1/L2. (C) Blockade of PD-1 and PD-L1 could be a therapeutic approach for enhancing immune cell function. Lymphoma cells might also be responsive to immunotherapy with antibodies that block CD47/SIRP (signal-regulatory protein) α interaction. Immune and inflammatory cell infiltrates in the TME produce molecules that bind to proteins expressed on the tumor cell membranes. The NF-κB, NOTCH1, and JAK-STAT pathways are activated via membrane-bound signaling. These TME pathways promote an inflammatory immune environment and resistance to apoptosis. Tumor infiltration by TAMs, immunosuppressive myeloid cells, and regulatory T cell may be related to the resistance to checkpoint blockade therapy (CBT). The mechanisms of resistance to PD-1 blockade have been identified in solid tumors partly,47,48 whereas they remain largely unknown in lymphoid malignancies. In solid tumors, a heavy infiltration of immune-suppressive myeloid cells can correlate with resistance to checkpoint blockade.49 Therefore, the characterization of the cHL microenvironment with a specific focus on inflammatory and immune cells might provide important information on the mechanisms of response to CBT.11,23 Furthermore, mutational analysis and clonal evolution measured by sequencing circulating cell-free tumor DNA may help identify the genetic determinants of resistance/refractoriness to anti–PD-1 therapy.50-52 Adapted and modified from Carbone and Gloghini.43
