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.
Highlights
Immune checkpoint molecules (ICPMs) modulate innate or adaptive immune responses [1,2,3,4]
We summarize the current state of the art of these compounds, including avelumab, which is the only immune checkpoint inhibitors (ICIs) targeting an immune checkpoint molecule ligand (ICPML) with preserved effector functions that has gained approval so far
ICPMs form ligand-receptor pairs, with the receptors being predominantly expressed on immune cells and the ligands being predominantly expressed on antigen-presenting cells (APC), tumor cells or other cell types [5]
Summary
Immune checkpoint molecules (ICPMs) modulate innate or adaptive immune responses [1,2,3,4]. Several monoclonal antibodies (mAb) against inhibitory ICPMs, generally referred to as immune checkpoint inhibitors (ICIs), have received regulatory approval and have yielded favorable therapeutic effects in a significant fraction of patients affected by several tumor types [5,7,8]. In this article we summarize the role of tumor cell-associated ICPMLs in tumor biology as well as the approaches that are being pursued in order to obtain compounds that deplete tumor cells expressing ICPMLs. We will not address here neither the effects of ICPMs on antitumor immune responses nor the clinical results obtained so far with ICIs. There are excellent reviews that cover these aspects, several of which are cited throughout this article
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