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.

Keywords: combination therapies; cytotoxic T-lymphocyte antigen 4; immune checkpoint; lymphoid neoplasms; monoclonal antibodies; programmed death 1.

Figure 1

Therapeutic approaches based on immune checkpoint blockade in B-cell lymphomas. Different therapeutic strategies to block PD-1/PD-L1 interaction are under clinical development in order to prevent PD-1-mediated attenuation of TCR signalling, allowing for activity restoration of exhausted CD8+ T-cells. CTLA-4 inhibition by monoclonal antibodies may induce tumour rejection through direct blockade of CTLA-4 competition for CD-80 (B7-1) and CD-86 (B7-2) ligands, which enhances CD28 costimulation and, thus, activation. Alternative immune checkpoint molecules expressed on tumour cells or immune cells in the TME can be simultaneously modulated to restore an effective antilymphoma immune response.

Figure 2

Clinical evolution of immune checkpoint-based therapies in B-cell lymphoma over the last 20 years (according to https://beacon-intelligence.com/checkpoint; data actualised in September 2020).

Figure 3

Mechanisms of resistance to immune checkpoint blockade. The deregulation of MHC class I components such as the loss of β2 microglobulin (B2M) and the loss of human leukocyte antigen (HLA) heterozygosity as well as defects in IFN signalling pathways may impair antigen recognition by antitumor CD8+ T-cells. Amplification of oncogenic signalling pathways such as PI3K/AKT/mTOR, Wnt/β-catenin, and MAPK increases the production of immunosuppressive cytokines, trigger T-cell exclusion from TME and may also result in resistance to immune checkpoint blockade. Epigenetic (histone acetylation or DNA methylation) and genetic (deleterious mutations) alterations are crucial triggers of gene expression disorders related to sustained T-cell exhaustion that could eventually cause the failure of immune checkpoint therapy. Moreover, myeloid-derived suppressor cells (MDSCs), Tregs, tumour-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) are major immunosuppressive cell types within the TME that may contribute to resistance to immune checkpoint blockade. Immunosuppressive molecules such as TGF-β and IFN-γ, secreted by tumour cells, myeloid cells and macrophages in the TME, may also suppress the functions of effector T-cells, rendering immune checkpoint blockade ineffective.