CD8+ T cell responses are critical for anti-tumor immunity. While extensively profiled in the tumor microenvironment, recent studies in mice identified responses in lymph nodes (LNs) as essential; however, the role of LNs in human cancer patients remains unknown. We examined CD8+ T cells in human head and neck squamous cell carcinomas, regional LNs, 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 tumor. After anti-PD-L1 immunotherapy, Tpex in uninvolved LNs 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 LNs, these response hallmarks were impaired, with immunosuppressive cellular niches. Our results identify important roles for LNs in anti-tumor immune responses in humans. [Display omitted] • Tpex are abundant in uiLNs and clonally related to Tex-term in the TME • After anti-PD-L1 treatment, activated Tpex and Tex-int localize near DCs in uiLNs • uiLN anti-PD-L1 responses coincide with increased circulating Tex-int • Tpex and Tex-int responses to anti-PD-L1 therapy are disrupted in metLNs A study of CD8+ T cell populations in human head and neck squamous cell carcinomas identifies a role for lymph nodes in modulating anti-tumor responses in response to immunotherapy. [ABSTRACT FROM AUTHOR]