Depleting Tumor Cells Expressing Immune Checkpoint Ligands—A New Approach to Combat Cancer

Abstract

Antibodies against inhibitory immune checkpoint molecules (ICPMs), referred to as immune checkpoint inhibitors (ICIs), have gained a prominent place in cancer therapy. Several ICIs in clinical use have been engineered to be devoid of effector functions because of the fear that ICIs with preserved effector functions could deplete immune cells, thereby curtailing antitumor immune responses. ICPM ligands (ICPMLs), however, are often overexpressed on a sizeable fraction of tumor cells of many tumor types and these tumor cells display an aggressive phenotype with changes typical of tumor cells undergoing an epithelial-mesenchymal transition. Moreover, immune cells expressing ICPMLs are often endowed with immunosuppressive or immune-deviated functionalities. Taken together, these observations suggest that compounds with the potential of depleting cells expressing ICPMLs may become useful tools for tumor therapy. In this article, we summarize the current state of the art of these compounds, including avelumab, which is the only ICI targeting an ICPML with preserved effector functions that has gained approval so far. We also discuss approaches allowing to obtain compounds with enhanced tumor cell-depleting potential compared to native antibodies. Eventually, we propose treatment protocols that may be applied in order to optimize the therapeutic efficacy of compounds that deplete cells expressing ICPMLs.

Dysfunctional natural killer cells can be reprogrammed to regain anti-tumor activity

“…On this note, depletion of dysfunctional cells from the TME was suggested to improve therapeutic efficacy. Our study provides a novel strategy for in situ reprogramming of these dysfunctional cells rather than depleting them (Marcucci and Rumio, 2021 ; Cook and Whitmire, 2013 ). We describe a potential platform for this approach using an NP drug delivery system (Biber et al, 2021 ) (Fig.…”

Immunotherapy Based on Immune Checkpoint Molecules and Immune Checkpoint Inhibitors in Gastric Cancer–Narrative Review

“…Their depletion improves antitumour T cell responses and reduces tumour growth, a phenomenon that can be mediated by ICPMs [ 44 , 45 ]. Indeed, ICPMs can increase the production of suppressive cytokines and promote cytolysis, metabolic arrest, and dendritic cell (DC) suppression [ 46 , 47 ]. Thus, targeting Tregs can be an effective approach for immunotherapy and encompasses numerous methods, such as lowering the number of Tregs, suppressing their function and disrupting Treg recruitment to the tumour microenvironment [ 45 ].…”

Mechanisms of immune modulation in the tumor microenvironment and implications for targeted therapy

“…They can be divided into two classes: ICIs that co-stimulate [TNF family members, CD27, 4-1BB (CD137), OX40 (CD134), herpesvirus entry mediator (HVEM), CD30, and glucocorticoid-induced TNFR-related protein (GITR)] ( 110 ) and ICIs that inhibit immune responses ( 111 ) such as PD-1, PD-L1, CTLA-4, VISTA, TIM-3, TIGIT, HLA-G and LAG-3 ( Figure 1 ). ICIs form ligand-receptor pairs with other molecules, the receptors are mostly expressed on immune cells, while the ligands are mostly expressed on antigen-presenting cells, tumor cells, or other cell types, ( 112 ). Overexpression of these ligands on tumor cells can be the result of cell-autonomous stimuli or of stimuli from the TME.…”