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. We examined CD8+ T cells in human head and neck squamous cell carcinomas, regional LN, and blood using mass cytometry, single-cell genomics, and multiplexed ion beam imaging. We identified progenitor exhausted CD8+ T cells (Tpex) that were abundant in uninvolved LN and clonally related to terminally exhausted cells in the TME. After anti-PD-L1 immunotherapy, Tpex in uninvolved LN reduced in frequency but localized near dendritic cells and proliferating intermediate-exhausted CD8+ T cells (Tex-int), consistent with activation and differentiation. LN responses coincided with increased circulating Tex-int. In metastatic LN, these response hallmarks were impaired by immunosuppressive cellular niches. Our results identify important roles for LN in anti-tumor immune responses in humans.