Blockade of novel immune checkpoints and new therapeutic combinations to boost antitumor immunity

Abstract

Immunotherapy has emerged as a promising strategy for boosting antitumoral immunity. Blockade of immune checkpoints (ICs), which regulate the activity of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells has proven clinical benefits. Antibodies targeting CTLA-4, PD-1, and PD-L1 are IC-blockade drugs approved for the treatment of various solid and hematological malignancies. However, a large subset of patients does not respond to current anti-IC immunotherapy. An integrative understanding of tumor-immune infiltrate, and IC expression and function in immune cell populations is fundamental to the design of effective therapies. The simultaneous blockade of newly identified ICs, as well as of previously described ICs, could improve antitumor response. We review the potential for novel combinatory blockade strategies as antitumoral therapy, and their effects on immune cells expressing the targeted ICs. Preclinical evidence and clinical trials involving the blockade of the various ICs are reported. We finally discuss the rationale of IC co-blockade strategy with respect to its downstream signaling in order to improve effective antitumoral immunity and prevent an increased risk of immune-related adverse events (irAEs).

Keywords: Cytotoxic T lymphocytes; Immune checkpoint; Immunotherapy; NK cells; Tumor microenvironment.

Fig. 1

Coinhibitory receptors expressed by cytotoxic T lymphocytes (A) and natural killer cells (B) and their ligands. Cytotoxic T lymphocytes and natural killer cells can express multiple coinhibitory receptors, known as immune checkpoints, that produce downstream inhibitory signals when activated upon binding to their ligands. Note that not all ICs are expressed simultaneously by cytotoxic T lymphocytes or NK cells

Fig. 2

Immune checkpoint downstream inhibitory signaling in CD8⁺ T cells. Immune checkpoint pathways initiated after binding of ligands to their respective IC receptors (blue boxes) interfere with TCR signaling by a variety of mechanisms. ICs have inhibitory motifs in their cytoplasmic tail that can recruit (blue arrows) protein tyrosine phosphatases SHP1 and/or SHP2, which are responsible for dephosphorylating (red inhibitory arrows) TCR downstream signaling proteins. This is the case for PVRIG, 2B4, Siglec-7/−9, ILT2, BTLA, KIR-L, NKG2A, TIGIT, PD-1, and KLRG1. However, some ICs, such as CTLA-4, TIM-3, CD47, and CD200R1, present alternative downstream mechanisms, while other IC downstream signaling, such as that involving LAG-3, VISTA, CD96, CD160, and B7-H3, remains to be fully elucidated. Schematic representation of (A) SHP1-dependent inhibition of TCR signaling, (B) SHP2-dependent inhibition of TCR signaling, and (C) non-dependent SHP1 and SHP2 inhibition of TCR signaling. Dotted lines indicate indirect mechanisms (created with BioRender.com)