TGF-ß neutralization attenuates tumor residency of activated T cells to enhance systemic immunity in mice.

ABSTRACT

A tissue resident-like phenotype in tumor infiltrating T cells can limit systemic anti-tumor immunity. Enhanced systemic anti-tumor immunity is observed in head and neck cancer patients after neoadjuvant PD-L1 immune checkpoint blockade (ICB) and transforming growth factor ß (TGF-ß) neutralization. Using T cell receptor (TCR) sequencing and functional immunity assays in a syngeneic model of oral cancer, we dissect the relative contribution of these treatments to enhanced systemic immunity. The addition of TGF-ß neutralization to ICB resulted in the egress of expanded and exhausted CD8+ tumor infiltrating lymphocytes (TILs) into circulation and greater systemic anti-tumor immunity. This enhanced egress associated with reduced expression of Itgae (CD103) and its upstream regulator Znf683. Circulating CD8+ T cells expressed higher Cxcr3 after treatment, an observation also made in samples from patients treated with dual TGF-ß neutralization and ICB. These findings provide the scientific rationale for the use of PD-L1 ICB and TGF-ß neutralization in newly diagnosed patients with carcinomas prior to definitive treatment of locoregional disease.