Can allosteric receptor-protein interactions in receptor complexes be a molecular mechanism involved in cancer immune therapy?
- 1Department of Neuroscience, Karolinska Institutet, Sweden
Based on the work in the Central Nervous System with discoveries of allosteric receptor-receptor interactions in homo-and heteroreceptor complexes representing a major integrative mechanism in synapses and extrasynaptic regions, it is proposed that a similar mechanism exists in the immunological synapses. We discuss a putative additional molecular mechanism for the ability of the inhibitory T cell signaling proteins CTLA-4 and PD-1 and the adenosine A2AR to diminish T cell activation leading to enhancement of cancer development. We suggest that in the same immunological synapse involving T cells and antigen presenting cells multiple heteroreceptor complexes can participate and be in balance with each other. Their composition can vary between functional states and among different types of T cells. The T cell receptor (TCR) and its accelerators, strongly enhancing T cell activation, can be under inhibitory control by T cell signaling proteins CTLA4 and PD-1 and also the adenosine A2AR through inhibitory allosteric receptor-receptor interactions in different types of heteroreceptor complexes. As a result inhibitory tumor induced immunosuppression develops due to a dominance of the inhibitory signaling causing a brake on the TCR and/or its accelerator and the cancer immunotherapy becomes blocked.
Keywords: A2AR-TCR heteroreceptor complexes, cancer immunotherapy, T cell, Immunosuppression, G protein-coupled receptors (GPCR), Allosteric receptor-receptor interactions
Received: 02 Apr 2019;
Accepted: 06 Aug 2019.
Edited by:Steven G. Gray, St. James's Hospital, Ireland
Reviewed by:Leigh Stoddart, University of Nottingham, United Kingdom
Pierre De Meyts, Duve Institute, Catholic University of Louvain, Belgium
Copyright: © 2019 Borroto-Escuela and Fuxe. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mx. Dasiel O. Borroto-Escuela, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden, firstname.lastname@example.org