Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy

Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity. [Display omitted] •Neoadjuvant ICB induces local and systemic T cell responses in oral cancer patients•Treatment-responsive T cell clones recognize self-antigens including tumor antigens•Responding T cells in tumors display a tissue-resident memory program•Circulating PD-1+KLRG1-CD8 T cell frequency correlates with pathological response Analysis of immune cell kinetics in oral cancer patients responding to neoadjuvant immune checkpoint blockade identifies diverse features in circulating and tumor-infiltrating T cell subpopulations that underlie rapid response to therapy and correlate with pathological outcome.