Continuous replenishment of the dysfunctional CD8 T cell axis is associated with response to chemoimmunotherapy in...

Chemotherapy combined with immune checkpoint blockade has shown clinical activity in breast cancer. Response, however, occurs in only a low proportion of patients. How the immune landscape of the tumor determines the immune and clinical responses to chemoimmunotherapy is not well understood. Here, using a combination of single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq), we profile 40 biopsies from 27 patients with metastatic triple-negative breast cancer (TNBC), receiving chemotherapy and anti-PD-L1 alone or in combination with anti-CD73, in a phase 2 randomized clinical trial. Our results show an enrichment of late-dysfunctional, clonally expanded CD8⁺ T cells in responder (R) patients. On treatment, R display an influx of newly emerging clonotypes, as well as expansion of the CD8⁺ precursors. Collectively, our data suggest that baseline clonal expansion could be a potential predictor of response and that both clonal reinvigoration of pre-existing tumor-reactive T cells and clonal replacement on-treatment are important for a protective response to chemoimmunotherapy.