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.
JAML promotes CD8 and γδ T cell antitumor immunity and is a novel target for cancer immunotherapy
Disclosures: T.S. Young reported grants from AbbVie during the conduct of the study, and personal fees from AbbVie, Shoreline Bio, and Qihan Bio outside the submitted work. No other disclosures were reported.
W.L. Havran died in January 2020.
- Award Group:
- Funder(s): National Institutes of Health
- Award Ids(s): AI064811
- Award Group:
- Funder(s): Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research Institute
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Joseph M. McGraw, Flavian Thelen, Eric N. Hampton, Nelson E. Bruno, Travis S. Young, Wendy L. Havran, Deborah A. Witherden; JAML promotes CD8 and γδ T cell antitumor immunity and is a novel target for cancer immunotherapy. J Exp Med 4 October 2021; 218 (10): e20202644. doi: https://doi.org/10.1084/jem.20202644
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