Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating Tcells following neoadjuvant immunotherapy in head and neck cancer.

Abstract

Neoadjuvant immunotherapies (NITs) have led to clinical benefits in several cancers. Characterization of the molecular mechanisms underlying responses to NIT may lead to improved treatment strategies. Here we show that exhausted, tumor-infiltrating CD8+ T (Tex) cells display local and systemic responses to concurrent neoadjuvant TGF-β and PD-L1 blockade. NIT induces a significant and selective increase in circulating Tex cells associated with reduced intratumoral expression of the tissue-retention marker CD103. TGF-β-driven CD103 expression on CD8+ Tcells is reversed following TGF-β neutralization invitro, implicating TGF-β in Tcell tissue retention and impaired systemic immunity. Transcriptional changes implicate Tcell receptor signaling and glutamine metabolism as important determinants of enhanced or reduced Tex treatment response, respectively. Our analysis illustrates physiological and metabolic changes underlying Tcell responses to NIT, highlighting the interplay between immunosuppression, tissue retention, and systemic anti-tumor immunity and suggest antagonism of Tcell tissue retention as a promising neoadjuvant treatment strategy.