Regulation and Functions of Protumoral Unconventional T Cells in Solid Tumors

SIMPLE SUMMARY: While the biology of unconventional T cells has been extensively studied in the context of infection, their role in tumor immunity has only recently emerged. In this review, we provide an overview of the current knowledge pointing towards protumoral functions of unconventional T cells in solid cancer. The tumor microenvironment factors that shape and control these deleterious properties are also reviewed. Finally, we discuss how these elements may be considered as future targets in cancer immunotherapy and the outstanding questions in the field. ABSTRACT: The vast majority of studies on T cell biology in tumor immunity have focused on peptide-reactive conventional T cells that are restricted to polymorphic major histocompatibility complex molecules. However, emerging evidence indicated that unconventional T cells, including γδ T cells, natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are also involved in tumor immunity. Unconventional T cells span the innate–adaptive continuum and possess the unique ability to rapidly react to nonpeptide antigens via their conserved T cell receptors (TCRs) and/or to activating cytokines to orchestrate many aspects of the immune response. Since unconventional T cell lineages comprise discrete functional subsets, they can mediate both anti- and protumoral activities. Here, we review the current understanding of the functions and regulatory mechanisms of protumoral unconventional T cell subsets in the tumor environment. We also discuss the therapeutic potential of these deleterious subsets in solid cancers and why further feasibility studies are warranted.