The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas

• Published in: Cancers 2021-09, Vol.13 (18), p.4683
• Main Authors: Garcia-Lacarte, Marcos, Grijalba, Sara C., Melchor, Javier, Arnaiz-Leché, Adrián, Roa, Sergio
• Format: Article
• Language: English
• Subjects: Antigen presentation; Antigens; Apoptosis; B-cell lymphoma; CD8 antigen; Cell proliferation; Clonal selection; Cytokines; Cytotoxicity; Epigenetics; Gene expression; Germinal centers; Helper cells; Immune response (humoral); Immunotherapy; Interleukin 10; Interleukin 21; Ligands; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Microenvironments; PD-1 protein; PD-L1 protein; Positive selection; Review; T cell receptors; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13184683

Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (TFH) and regulatory T (TFR) or B (Breg) cells are involved in positive selection of GC B cells and may result critical in the lymphoma microenvironment. Here, we discuss a role of PD-1/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of TFR cells and limiting IL-21-mediated anti-tumour functions of TFH cells and maximize the use of PD-1/PD-L1 signaling to escape from CD8+ cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1/PD-L1-based combinational immunotherapies in DLBCL.