Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes
Maha K. Rahim, Trine Line Hauge Okholm, Kyle B. Jones, Elizabeth McCarthy, Candace C. Liu, Jacqueline L. Yee, Stanley Tamaki, Diana M. Marquez, Iliana Tenvooren, Katherine C. Wai, Alexander Cheung, Brittany Davidson, Vrinda Johri, Bushra Samad, William O’Gorman, Matthew F. Krummel, Annemieke van Zante, Alexis J. Combes, Michael Angelo, Lawrence Fong, Alain P. Algazi, Patrick K. Ha, Matthew H. Spitzer
Abstract
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.