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 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.
Cell. 2023 Mar 16;186(6):1127-1143.e18. doi: 10.1016/j.cell.2023.02.021.
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.
CD8 T 细胞反应对于抗肿瘤免疫至关重要。虽然在肿瘤微环境中得到了广泛研究，但最近在小鼠中的研究发现淋巴结（LNs）中的反应是必不可少的；然而，LN 在人类癌症患者中的作用仍不清楚。我们使用质谱流式细胞术、单细胞基因组学和多重离子束成像技术，在人类头颈部鳞状细胞癌、局部淋巴结和血液中检查了 CD8 T 细胞。我们鉴定了在未受累的 LN 中丰富存在的祖细胞耗竭 CD8 T 细胞（Tpex），并且与肿瘤中终末耗竭细胞克隆相关。在抗 PD-L1 免疫治疗后，未受累 LNs 中的 Tpex 频率降低，但定位于树突状细胞附近并增殖中间耗竭的 CD8 T 细胞（Tex-int），与激活和分化一致。LN 反应伴随着循环 Tex-int 的增加。在转移性 LNs 中，这些反应特征受损，存在免疫抑制细胞龛。我们的研究结果确定了 LNs 在人类抗肿瘤免疫反应中的重要作用。
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