The PD-1/PD-L1 checkpoint in normal germinal centers and diffuse large B-cell lymphomas

Journal article : Review

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 (T_FH) and regulatory T (T_FR) or B (B_reg) 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 T_FR cells and limiting IL-21-mediated anti-tumour functions of T_FH 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.

Authors: Garcia-Lacarte, M; Grijalba, SC; Melchor, J; Arnaiz-Leché, A; Roa, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: Cancers
• Volume: 13
• Issue: 18
• Article number: 4683
• Place of publication: Switzerland
• Publication date: 2021-09-18
• Acceptance date: 2021-09-13
• DOI: 10.3390/cancers13184683
• EISSN: 2072-6694
• Pmid: 34572910
• Language: English
• Keywords: GC B cells; T follicular helper cells; combination immunotherapy; T follicular regulatory cells; lymphoma; immune checkpoint; germinal center; B regulatory cells
• Subtype: Review