Intracellular radar: Understanding γδ T cell immune surveillance and implications for clinical strategies in oncology

Abstract

T cells play a key role in anticancer immunity, with responses mediated through a diversity of αβ or γδ T cell receptors. Although αβ and γδ T cells stem from common thymic precursors, the development and subsequent biological roles of these two subsets differ considerably. γδ T cells are an unconventional T cell subset, uniquely poised between the adaptive and innate immune systems, that possess the ability to recognize intracellular disturbances and non-peptide-based antigens to eliminate tumors. These distinctive features of γδ T cells have led to recent interest in developing γδ-inspired therapies for treating cancer patients. In this minireview, we explore the biology of γδ T cells, including how the γδ T cell immune surveillance system can detect intracellular disturbances, and propose a framework to understand the γδ T cell-inspired therapeutic strategies entering the clinic today.

Keywords: anticancer; chimeric antigen receptor; clinical; gamma delta (γδ) T cells; immunotherapy; intracellular; surveillance; γδT.

Figure 1

γδ T Cell Detection of Intracellular Stress. A collection of sentry proteins monitor the intracellular space for specific molecular signs of stress, including butyrophilins monitoring for phosphoantigen levels, MR1 monitoring for small metabolites indicative of tumor development or cancer, and CD1 monitoring for lipids. By interacting with these protein sentries, γδ T cells can detect when a cell is under stress and initiate an effector response.

Figure 2

γδ T Cell-Inspired Clinical Strategies. (A) γδ T cell biology may be employed to eliminate tumors by four different strategies. In strategy 1, endogenous γδ T cells kill the tumor. In strategy 2, exogenous engineered γδ T cell therapies kill the tumor. In strategy 3, γδ T cell receptor biology is used to recruit an endogenous αβ T cell adaptive response to stressed tumor cells. In strategy 4, γδ T cell receptor biology is used as a targeting strategy for traditional αβ CAR-T cells to identify and attack stressed tumor cells. In each of these strategies, researchers can either employ validated protein constructs (e.g., CARs using GP3C – 4-1BB – CD3ζ from Adicet) or engineer innovative protein structures (e.g., fusion protein chains of CD19 – Fc – BTN3A1/BTN2A1 from Shattuck Labs) to maximize anti-tumor activity. (B) Researchers and companies leading investigation into each clinical strategy.