Immune Checkpoint Receptors Signaling in T Cells

Abstract

The characterization of the receptors negatively modulating lymphocyte function is rapidly advancing, driven by success in tumor immunotherapy. As a result, the number of immune checkpoint receptors characterized from a functional perspective and targeted by innovative drugs continues to expand. This review focuses on the less explored area of the signaling mechanisms of these receptors, of those expressed in T cells. Studies conducted mainly on PD-1, CTLA-4, and BTLA have evidenced that the extracellular parts of some of the receptors act as decoy receptors for activating ligands, but in all instances, the tyrosine phosphorylation of their cytoplasmatic tail drives a crucial inhibitory signal. This negative signal is mediated by a few key signal transducers, such as tyrosine phosphatase, inositol phosphatase, and diacylglycerol kinase, which allows them to counteract TCR-mediated activation. The characterization of these signaling pathways is of great interest in the development of therapies for counteracting tumor-infiltrating lymphocyte exhaustion/anergy independently from the receptors involved.

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy

“…A balance of positive and negative signals tunes the immune reactivity of T lymphocytes [ 55 , 56 ]. To avoid immune-mediated tissue damage and autoimmunity, the signals generated by immunoreceptors must be tightly controlled by negative signals [ 55 ].…”

“…Conversely, inhibitory receptors signal via Tyr phosphatases (e.g., SHP-2) to metabolize DAG and via PI phosphatases (e.g., SHIP-1). The joined inhibitory action of PD-1 on the PI3K/AKT and the MAPK pathway results in transcriptional modulation of cell cycle progression [ 55 , 56 ].…”

“…Resistance mechanisms of TILs from solid tumors to ICI have been described [ 55 ]. They have to do with negative receptor signaling in T cells [ 56 ].…”

“…Following cell entry, NDV targets the cap-dependent translational machinery through the MNK1/2-eIF4E axis [ 93 ]. Tumor-selective virus replication then occurs in autophagosomes [ 56 ]. F and HN proteins play important roles in virus release and immune cell activation.…”

“…(ii) use of IL15 in cell-based cancer immunotherapy [ 139 ], (iii) immunotherapy of TAA positive common solid cancers with natural high-avidity TCR-engineered T cells [ 140 ], (iv) improvement of immunotherapeutic efficacy against solid tumors in mice with dual-specific chimeric antigen receptor (CAR) T cells expanded in vitro with TCR reactivity against OV encoded antigens [ 141 ]. Illustrations of the fight of T cells against tumor cells can be seen from several references of this publication [ 2 , 11 , 13 , 23 , 28 , 56 , 113 , 137 ].…”