Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy

Abstract

Summary In the past decade, the power of harnessing T cell co-signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR-Ts) and second, re-animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re-ignite T cell immunity, in order to eradicate tumors. In transplantation, there is also great interest in targeting T cell co-signaling, but with the opposite goal: in this field, we seek the Yin to cancer immunotherapy’s Yang, and focus on manipulating T cell co-signaling to induce tolerance rather than activation. In this review, we discuss the major T cell signaling pathways that are being investigated for tolerance-induction, detailing pre-clinical studies and the path to the clinic for many of these molecules. These include blockade of co-stimulation pathways and agonism of coinhibitory pathways, in order to achieve the delicate state of balance that is transplant tolerance: a state which guarantees lifelong transplant acceptance without ongoing immunosuppression, and with preservation of protective immune responses. In the context of the clinical translation of immune tolerance strategies, we discuss the significant challenge that is embodied by the fact that targeted pathway modulators may have opposing effects on tolerance based on their impact on effector versus regulatory T cell biology. Achieving this delicate balance holds the key to the major challenge of transplantation: lifelong control of alloreactivity while maintaining an otherwise intact immune system.

Introduction to checkpoint inhibitors and cancer immunotherapy

“…According to this model, T cell activation requires a first signal provided by provided by interaction of antigenic peptide/MHC complex with the T cell receptor (TCR), which confers specificity to the response, and a second antigen‐independent costimulatory signal. The interaction between the CD28 costimulatory receptor and its ligands CD80 (B7‐1) and CD86 (B7‐2) fulfilled many requirements for the costimulatory signal envisioned by Lafferty and Cunningham (see this issue). However, the discovery of CTLA‐4 as a CD28 homolog that possessed potent inhibitory functions, dramatically changed our perception of the two signal model .…”

“…The interaction between the CD28 costimulatory receptor and its ligands CD80 (B7‐1) and CD86 (B7‐2) fulfilled many requirements for the costimulatory signal envisioned by Lafferty and Cunningham (see this issue). However, the discovery of CTLA‐4 as a CD28 homolog that possessed potent inhibitory functions, dramatically changed our perception of the two signal model . We now appreciate that there are a number of inhibitory (coinhibitory) as well as stimulatory (costimulatory) second signals that can modulate T cell receptor (TCR)—mediated T signals.…”

“…T cell costimulatory and coinhibitory pathways provide critical checkpoints that regulate adaptive immunity. T cell costimulatory pathways fall into two major families, the Ig superfamily which includes CD28, ICOS, TMIGD2 (IGPR‐1/CD28H) (which are CD28 family members) and CD226, and TNF:TNR receptor family, which includes Ox40 and 4‐1BB . There is an abundance of inhibitory checkpoints which can influence T cell responses.…”

“…Second, the cell‐type specific functions of checkpoint molecules are only beginning to be understood. There is an increasing appreciation of the opposing effects of checkpoint pathway modulators on effector and regulatory T cells . This poses challenges for clinical translation of immune tolerance strategies, and the need to induce tolerance in all T cell subpopulations, both effector and regulatory .…”

“…Some checkpoint receptors such as Tim‐3 are expressed on myeloid cells as well as T cells, suggesting roles on innate and adaptive immunity. Finally, inhibitory checkpoint blockade carries the risk of autoimmune adverse events, given the roles of inhibitory checkpoint molecules in T cell tolerance . A better understanding of how to uncouple anti‐tumor activity from loss of self tolerance is necessary to increase therapeutic efficacy of checkpoint blockade.…”