Abstract
Simple SummaryThe PD-1/PD-L1 axis is not only involved in anti-tumour immune evasion of germinal center (GC)-derived diffuse large B cell lymphomas (DLBCL), but also inherently in the fine-tuned regulation of normal GC reactions during humoral immune responses. This checkpoint axis modulates crosstalks between B and T cells that allow positive selection for survival and proliferation. Malignant DLBCL cells may deceive and take advantage of these mechanisms to establish an immunosuppressive microenvironment. This review delves into PD-1/PD-L1 role in the complex inter-cellular interactions from normal GC reactions to DLBCL progression, in order to highlight vulnerabilities that could be targeted by promising combination immunotherapies.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.
Highlights
Interest in the immune-checkpoint protein programmed death 1 (PD-1), in T lymphocytes, and its ligand (PD-L1), in lymphoma B cells, have increased in parallel to the remarkable clinical outcomes demonstrated with their blockade in a broad range of tumour types [1]
We describe major evidence for naturally occurring PD-1/PD-L1 signaling to fine modulate germinal center (GC) reactions and discuss evidences for how GC-derived malignant cells may exploit this immune-checkpoint to facilitate selection and survival first, and elude anti-tumour immune responses later at advanced diffuse large B cell lymphoma (DLBCL)
As a result of the accumulation and selection of the above discussed traits, a more advanced scenario could be described where DLBCL cells have consolidated their ability for immune evasion, taking advantage of (i) preserved “select me” and “do not kill me” signals inherited from the GC B cell-of-origin, and (ii) extended mechanisms that further contribute to impaired T cell infiltration and/or cytotoxic functions (Figure 2, right)
Summary
Interest in the immune-checkpoint protein programmed death 1 (PD-1), in T lymphocytes, and its ligand (PD-L1), in lymphoma B cells, have increased in parallel to the remarkable clinical outcomes demonstrated with their blockade in a broad range of tumour types [1]. PD-1 can dampen T cell receptor (TCR) ligand sensitivity [32,33] and thereby help to promote affinity-based selection by TFH cells through enforcing a more stringent selection threshold for competing GC B cells [24] These studies support the idea that signaling through PD-1 by CD4+ TFH is essential to control both proper positioning and helper functions to GC responses (Figure 1, left). GCs reactions are controlled by helper signals that promote selection and proliferation, and by follicular regulatory T cells (TFR ) that suppress the magnitude and output of the GC response [42,43] (Figure 1, right). These TFR cells are a subset of CD4+. PD-1 has been described to be expressed in CD8+ TFR cells and to be necessary for their correct suppressive function [52], further supporting a fine-tuned involvement of PD-1/PD-L1 signaling in T cell regulatory functions
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