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

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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.

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Author and article information

Journal

Journal ID (iso-abbrev): Cell

Title: Cell

Publisher: Elsevier BV

ISSN (Electronic): 1097-4172

ISSN (Print): 0092-8674

Publication date (Electronic): Mar 16 2023

Volume: 186

Issue: 6

Affiliations

[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; 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.

[3 ] Department of Pathology, Stanford University, Stanford, CA 94304, USA.

[4 ] UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA.

[5 ] Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.

[6 ] Department of Translational Medicine, Genentech, Inc., South San Francisco, CA 94080, USA.

[7 ] 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.

[8 ] 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.

[9 ] 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.

[10 ] 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.

[11 ] 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.

[12 ] 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.

[13 ] 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.

Article

Mid ID: NIHMS1882713 Publisher Item ID: S0092-8674(23)00164-2

DOI: 10.1016/j.cell.2023.02.021

PMC ID: 10348701

PubMed ID: 36931243

SO-VID: 213921fb-4f5b-4d9e-9581-96d2e136f659

History

Keywords: CD8(+) T cells,lymph nodes,T cell exhaustion,cancer immunotherapy,immune checkpoint blockade

Data availability:

Keywords: CD8(+) T cells, lymph nodes, T cell exhaustion, cancer immunotherapy, immune checkpoint blockade

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