Tissue-resident Memory and Circulating T cells are Early Responders to Pre-surgical Cancer Immunotherapy

Pre-surgical (neoadjuvant) immune checkpoint blockade has shown promising activity in multiple cancer types, but the molecular mechanisms are not well understood. Here, we characterized early kinetic changes 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 phase 2 clinical trial. Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs compared to non-responding cells. These programs were already active in pre-treatment T cells that later responded, reflecting a capacity for rapid response. Treatment also induced a systemic immune response, including expansion of pre-existing and emergent T cell clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, including pretreatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response, and these activated cells were enriched for tumor-infiltrating T cell clonotypes. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity. Samples from 30 patients from 2 different cohorts (anti-PD-1 monotherapy, anti-PD-1+anti-CTLA-4 combination therapy)