Rahim, Okholm, and Jones et al. demonstrated the differential role of uninvolved (uiLNs) and metastatic (met-LNs) lymph nodes in orchestrating antitumor responses in human HNSCC. uiLNs were enriched in progenitor exhausted CD8+ T cells (Tpex) compared to primary tumors, which were enriched in clonally related exhausted CD8+ T cells (Tex). Anti-PD-L1 treatment decreased Tpex in human uiLNs and increased the frequency of proliferating PD-1+TCF-CD69+ CD8+ T cells (Tex-int) in both uiLNs and blood. In uiLNs, both Tpex and Tex-int were localized closely with DCs, and this interaction increased with ICB treatment. In met-LNs, Tpex and Tex-int were localized in immunosuppressive niches and didn’t respond to ICB.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University
Author Info: (1) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (3) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Pharma Technical Cell and Gene Therapy, Genentech, Inc., South San Francisco, CA 94080, USA. (4) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (5) Department of Pathology, Stanford University, Stanford, CA 94304, USA. (6) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (7) UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. (8) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (9) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (10) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (11) Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (12) UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. (13) UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. (14) UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. (15) Department of Translational Medicine, Genentech, Inc., South San Francisco, CA 94080, USA. (16) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (17) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. (18) UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. (19) Department of Pathology, Stanford University, Stanford, CA 94304, USA. (20) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (21) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (22) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (23) Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: matthew.spitzer@ucsf.edu.
