Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes,Cell

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Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes
Cell ( IF 64.5 ) Pub Date : 2023-03-16 , DOI: 10.1016/j.cell.2023.02.021
Maha K Rahim ₁ , Trine Line H Okholm ₁ , Kyle B Jones ₂ , Elizabeth E McCarthy ₁ , Candace C Liu ₃ , Jacqueline L Yee ₁ , Stanley J Tamaki ₄ , Diana M Marquez ₁ , Iliana Tenvooren ₁ , Katherine Wai ₁ , Alexander Cheung ₅ , Brittany R Davidson ₄ , Vrinda Johri ₄ , Bushra Samad ₄ , William E O'Gorman ₆ , Matthew F Krummel ₇ , Annemieke van Zante ₈ , Alexis J Combes ₉ , Michael Angelo ₃ , Lawrence Fong ₁₀ , Alain P Algazi ₁₁ , Patrick Ha ₁₂ , Matthew H Spitzer ₁₃

Affiliation

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.
Department of Pathology, Stanford University, Stanford, CA 94304, USA.
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 Translational Medicine, Genentech, Inc., South San Francisco, CA 94080, USA.
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.
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.
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.
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.
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.
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.
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.

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.

中文翻译：

人类区域淋巴结中对癌症免疫治疗的动态 CD8+ T 细胞反应在转移淋巴结中被破坏

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进行了广泛的研究，但最近对小鼠的研究发现淋巴结（LN）的反应至关重要；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检查了人类头颈部鳞状细胞癌、局部淋巴结和血液中的CD8 ^{+ T 细胞。}我们鉴定出祖细胞耗竭的 CD8 ⁺ T 细胞 (Tpex) 在未受累的淋巴结中大量存在，并且与肿瘤中终末耗竭的细胞克隆相关。抗 PD-L1 免疫治疗后，未受累 LN 中的 Tpex 频率降低，但局限于树突状细胞和增殖的中度耗尽 CD8 ⁺ T 细胞 (Tex-int)，这与激活和分化一致。LN 反应与循环 Tex-int 增加同时发生。在转移性淋巴结中，这些反应标志受到损害，并出现免疫抑制细胞生态位。我们的结果确定了 LN 在人类抗肿瘤免疫反应中的重要作用。

更新日期：2023-03-17

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