Targeting the Immune Microenvironment in Lymphomas of B-Cell Origin: From Biology to Clinical Application

Abstract

In lymphomas of B-cell origin, cancer cells orchestrate an inflammatory microenvironment of immune and stromal cells that sustain the tumor cell survival and growth, known as a tumor microenvironment (TME). The features of the TME differ between the different lymphoma types, ranging from extremely inflammatory, such as in Hodgkin lymphoma, to anergic, leading to immune deficiency and susceptibility to infections, such as in chronic lymphocytic leukemia. Understanding the characteristic features of the TME as well as the interactions between cancer and TME cells has given insight into the pathogenesis of most lymphomas and contributed to identify novel therapeutic targets. Here, we summarize the preclinical data that contributed to clarifying the role of the immune cells in the TME of different types of lymphomas of B-cell origin, and explain how the understanding of the biological background has led to new clinical applications. Moreover, we provide an overview of the clinical results of trials that assessed the safety and efficacy of drugs directly targeting TME immune cells in lymphoma patients.

Keywords: B-cell lymphoma; CD47; Hodgkin lymphoma; PD-1; PD-L1; T cells; immune cells; macrophages; tumor microenvironment.

Figure 1

Common immune microenvironment patterns in lymphomas of B-cell origin. Left panel: cHL, PMBCL and PCNSL/PTL share the feature of genetic aberrations in the 9p24.1 locus leading to an intrinsic overexpression of PD-L1, which is associated with a good clinical response to PD-1 blockade. Middle panel: DLBCL and FL show remnants of the germinal center in their immune microenvironment and share the potential to clinically respond to CD47 blockade. Right panel: CLL has a distinct immune microenvironment which is markedly protective. BCR-inhibiting drugs release CLL cells from this niche. SIRPα = Signal regulatory protein α.