Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted by metastasis

CD8+ T cell responses are critical for anti-tumor immunity. While extensively profiled in the tumor microenvironment (TME), recent studies in mice identified responses in lymph nodes (LN) as essential; however, the role of LN in human cancer patients remains unknown. Here, we examined CD8+ T cells in human head and neck squamous cell carcinomas (HNSCC) and regional lymph node (LN) using single-cell genomics. We identified progenitor exhausted CD8+ T cells (TCF7 Exhausted) that were clonally related to terminally exhausted CD8 T cells in the TME. Our results identify an important role for the LN as a reservoir of more functional CD8+ T cells for anti-tumor immune responses in humans. We performed scRNA sequencing to understand how the tissue compartment (lymph node versus tumor) affects T cell phenotype in the context of head and neck squamous cell carcinoma (HNSCC). We used a combination of scRNA-sequencing + scTCR-sequencing and CITE-sequencing, which obtains measurements at both the protein and transcriptome level for a subset of samples, + scTCR-sequencing to obtain TCR sequences to identify and phenotype shared clones in the tissue compartments.