Microenvironment Remodeling and Subsequent Clinical Implications in Diffuse Large B-Cell Histologic Variant of Richter Syndrome

Abstract

IntroductionRichter Syndrome (RS) is defined as the development of an aggressive lymphoma in the context of Chronic Lymphocytic Leukemia (CLL), with a Diffuse Large B-Cell Lymphoma (DLBCL) histology in 95% cases. RS genomic landscape shares only a few features with de novo DLBCLs and is marked by a wide spectrum of cytogenetic abnormalities. Little is known about RS microenvironment. Therapeutic options and efficacy are limited, leading to a 12 months median overall survival. The new targeted treatments usually effective in CLL fail to obtain long-term remissions in RS.MethodsWe reviewed available PubMed literature about RS genomics, PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) pathway triggering and subsequent new therapeutic options.ResultsData from about 207 patients from four landmark papers were compiled to build an overview of RS genomic lesions and point mutations. A number of these abnormalities may be involved in tumor microenvironment reshaping. T lymphocyte exhaustion through PD-L1 overexpression by tumor cells and subsequent PD-1/PD-L1 pathway triggering is frequently reported in solid cancers. This immune checkpoint inhibitor is also described in B lymphoid malignancies, particularly CLL: PD-1 expression is reported in a subset of prolymphocytes from the CLL lymph node proliferation centers. However, there is only few data about PD-1/PD-L1 pathway in RS. In RS, PD-1 expression is a hallmark of recently described « Regulatory B-cells », which interact with tumor microenvironment by producing inhibiting cytokines such as TGF-β and IL-10, impairing T lymphocytes anti-tumoral function. Based upon the discovery of high PD-1 expression on tumoral B lymphocyte from RS, immune checkpoint blockade therapies such as anti-PD-1 antibodies have been tested on small RS cohorts and provided heterogeneous but encouraging results.ConclusionRS genetic landscape and immune evasion mechanisms are being progressively unraveled. New protocols using targeted treatments such as checkpoint inhibitors as single agents or in combination with immunochemotherapy are currently being evaluated.

The Determinants of B Cell Receptor Signaling as Prototype Molecular Biomarkers of Leukemia

“…Characterization of the molecular prognostic parameters and genomic landscape predict primary response but not relapse to treatment. Often, the underrated interactions between molecular cytogenetics features and the microenvironment specific survival signals mediated by direct contacts, adhesion molecules, chemokines and ligand-receptor interactions are of great prognostic value (15,(64)(65)(66). The kinases of BCR signaling pathway such as PI3K, BTK and SYK, are also involved in receptor mediated crosstalk (67).…”

Immunotherapeutic Strategies in Chronic Lymphocytic Leukemia: Advances and Challenges

“…For instance, interactions of PD1 with its ligand PD-L1 represent a major immune checkpoint engaged by tumor cells to avoid T-cell immune surveillance. From the biological standpoint, little is known about PD1/PD-L1 axis in RS, however studies show how, differently from CLL, tumor cells in RS overexpress PD1 thus determining an impairment of T lymphocytes anti-tumor functions; for such reasons the PD1/PD-L1 axis could be a valid candidate for immunotherapy of RS ( 105 ). In CLL, PD1 inhibitors used as single agents have so far provided disappointing therapeutic results ( 60 , 106 ), whereas the anti-PD1 mAb pembrolizumab has exhibited selective efficacy in patients with CLL transformed into RS ( 17 , 107 ).…”

Richter Transformation in Chronic Lymphocytic Leukemia: Update in the Era of Novel Agents

“…From this point of view, microenvironment remodeling also seems to have a role in the development of RT. This observation is reflected by a high programmed death 1 (PD-1) expression by tumoral B lymphocytes [55,56], higher programmed death ligand 1 (PD-L1) expression in histiocytes and dendritic cells, the higher infiltration of FOXP3-positive T cells and CD163-positive macrophages, and lower peripheral blood T-cell receptor clonality compared to CLL without RT [56], suggesting changes in the immune signature of CLL after RT.…”