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

Maha K Rahim; Trine Line H Okholm; Kyle B Jones; Elizabeth E McCarthy; Candace C Liu; Jacqueline L Yee; Stanley J Tamaki; Diana M Marquez; Iliana Tenvooren; Katherine Wai; Alexander Cheung; Brittany R Davidson; Vrinda Johri; Bushra Samad; William E O'Gorman; Matthew F Krummel; Annemieke van Zante; Alexis J Combes; Michael Angelo; Lawrence Fong; Alain P Algazi; Patrick Ha; Matthew H Spitzer

doi:10.1016/j.cell.2023.02.021

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

Cell. 2023 Mar 16;186(6):1127-1143.e18. doi: 10.1016/j.cell.2023.02.021.

Authors

Maha K Rahim¹, Trine Line H Okholm¹, Kyle B Jones², Elizabeth E McCarthy¹, Candace C Liu³, Jacqueline L Yee¹, Stanley J Tamaki⁴, Diana M Marquez¹, Iliana Tenvooren¹, Katherine Wai¹, Alexander Cheung⁵, Brittany R Davidson⁴, Vrinda Johri⁴, Bushra Samad⁴, William E O'Gorman⁶, Matthew F Krummel⁷, Annemieke van Zante⁸, Alexis J Combes⁹, Michael Angelo³, Lawrence Fong¹⁰, Alain P Algazi¹¹, Patrick Ha¹², Matthew H Spitzer¹³

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.

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.

Trial registration: ClinicalTrials.gov NCT03708224.

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

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
CD8-Positive T-Lymphocytes*
Humans
Immunotherapy / methods
Lymph Nodes
Mice
Neoplasms* / pathology
Neoplasms* / therapy
Tumor Microenvironment

Associated data

ClinicalTrials.gov/NCT03708224

Abstract

Publication types

MeSH terms

Associated data

Grants and funding