T cells are critical mediators of antitumor immunity and a major target for cancer immunotherapy. Antibody blockade of inhibitory receptors such as PD-1 can partially restore the activity of tumor-infiltrating lymphocytes (TILs). However, the activation signals required to promote TIL responses are less well characterized. Here we show that the antitumor activity of CD8 and γδ TIL is supported by interactions between junctional adhesion molecule–like protein (JAML) on T cells and its ligand coxsackie and adenovirus receptor (CXADR) within tumor tissue. Loss of JAML through knockout in mice resulted in accelerated tumor growth that was associated with an impaired γδ TIL response and increased CD8 TIL dysfunction. In mouse tumor models, therapeutic treatment with an agonistic anti-JAML antibody inhibited tumor growth, improved γδ TIL activation, decreased markers of CD8 TIL dysfunction, and significantly improved response to anti–PD-1 checkpoint blockade. Thus, JAML represents a novel therapeutic target to enhance both CD8 and γδ TIL immunity.

Antitumor immunity relies on the ability of T cells to recognize and kill tumor targets. γδ T cells are a specialized subset of T cells that predominantly localizes to non-lymphoid tissue such as the skin, gut, and lung where they are actively involved in tumor immunosurveillance. γδ T cells respond to self-stress ligands that are increased on many tumor cells, and these interactions provide costimulatory signals that promote their activation and cytotoxicity. This review will cover costimulatory molecules that are known to be critical for the function of γδ T cells with a specific focus on mouse dendritic epidermal T cells (DETC). DETC are a prototypic tissue-resident γδ T cell population with known roles in antitumor immunity and are therefore useful for identifying mechanisms that may control activation of other γδ T cell subsets within non-lymphoid tissues. This review concludes with a brief discussion on how γδ T cell costimulatory molecules can be targeted for improved cancer immunotherapy.

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