Dysfunctional states of unconventional T-cell subsets in cancer

Abstract Unconventional T cells represent a promising therapeutic agent to overcome the current limitations of immunotherapies due to their universal T-cell receptors, ability to respond directly to cytokine stimulation, and capacity to recruit and modulate conventional immune cells in the tumor microenvironment. Like conventional T cells, unconventional T cells can enter a dysfunctional state, and the functional differences associated with this state may provide insight into the discrepancies observed in their role in antitumor immunity in various cancers. The exhaustive signature of unconventional T cells differs from conventional αβ T cells, and understanding the differences in the mechanisms underlying exhaustive differentiation in these cell types may aid in the discovery of new treatments to improve sustained antitumor responses. Ongoing clinical trials investigating therapies that leverage unconventional T-cell populations have shown success in treating hematologic malignancies and reducing the immunosuppressive tumor environment. However, several hurdles remain to extend these promising results into solid tumors. Here we discuss the current knowledge on unconventional T-cell function/dysfunction and consider how the incorporation of therapies that modulate unconventional T-cell exhaustion may aid in overcoming the current limitations of immunotherapy. Additionally, we discuss how components of the tumor microenvironment alter the functions of unconventional T cells and how these changes can affect tumor infiltration by lymphocytes and alter conventional T-cell responses.