Immune-Checkpoint Inhibitors in B-Cell Lymphoma

Abstract

For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because, in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and build a projection of how the field may evolve in the near future. In particular, we will analyse the current strategies being evaluated both preclinically and clinically, with the aim of fostering the use of immune-checkpoint inhibitors in lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.

Heat Shock Proteins in Lymphoma Immunotherapy

“…NHL is classified into indolent (slowgrowing) and aggressive (fast-growing) lymphoma. The most common indolent lymphoma is follicular lymphoma (FL), while other slow-growing lymphoma subtypes include marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and lymphoplasmacytic lymphoma (94). The most common aggressive NHL subtype is represented by diffuse large B-cell lymphoma (DLBCL), while FIGURE 1 | Tumor microenvironment in cHL.…”

“…other aggressive lymphoma subtypes include mantle cell lymphoma (MCL), Burkitt lymphoma (BL) and primary effusion lymphoma (94).…”

Migration and Adhesion of B-Lymphocytes to Specific Microenvironments in Mantle Cell Lymphoma: Interplay between Signaling Pathways and the Epigenetic Landscape

“…These activated signaling pathways play a critical role in the inhibition of apoptosis, maintaining proliferation, survival and migration of MCL cells [6,44,45]. Crosstalk between tumor cells and microenvironment components promotes anti-tumor immune responses in B-cell lymphomas [46]. Interaction between CD40 on MCL cells and the CD40 ligand on the surface of T-cells in the microenvironment promotes tumor cell proliferation and induces PD-L1 (program-death ligand-1) expression on MCL cells [47,48].…”

Advances and Perspectives in the Treatment of B-Cell Malignancies

“…Armengol et al provide an exhaustive overview of the current arsenal of ICIs used in B-cell lymphomas, detailing their clinical evaluation and reported adverse events. The authors highlight the potential of combination immunotherapy involving PD-1/PD-L1 and CTLA-4 inhibitors, and anticipate the implementation of biomarker-driven trials where patient-specific profiling of cell subtypes and genomic alterations in the TME will identify optimal targets [ 4 ]. A well-established mechanism by which malignant B cells can evade anti-tumor immune responses is the overexpression of the oncogene MYC.…”