Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis

Bridget P Keenan; Elizabeth E McCarthy; Arielle Ilano; Hai Yang; Li Zhang; Kathryn Allaire; Zenghua Fan; Tony Li; David S Lee; Yang Sun; Alexander Cheung; Diamond Luong; Hewitt Chang; Brandon Chen; Jaqueline Marquez; Brenna Sheldon; Robin K Kelley; Chun Jimmie Ye; Lawrence Fong

doi:10.1016/j.celrep.2022.111384

Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis

Cell Rep. 2022 Sep 20;40(12):111384. doi: 10.1016/j.celrep.2022.111384.

Authors

Bridget P Keenan¹, Elizabeth E McCarthy², Arielle Ilano³, Hai Yang⁴, Li Zhang⁵, Kathryn Allaire³, Zenghua Fan³, Tony Li⁶, David S Lee⁶, Yang Sun⁷, Alexander Cheung¹, Diamond Luong³, Hewitt Chang³, Brandon Chen⁴, Jaqueline Marquez³, Brenna Sheldon⁸, Robin K Kelley¹, Chun Jimmie Ye⁹, Lawrence Fong¹⁰

Affiliations

¹ Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
² Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
³ Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA.
⁴ Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
⁷ Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁸ Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁹ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA; J. David Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Electronic address: jimmie.ye@ucsf.edu.
¹⁰ Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Electronic address: lawrence.fong@ucsf.edu.

Abstract

Suppressive myeloid cells can contribute to immunotherapy resistance, but their role in response to checkpoint inhibition (CPI) in anti-PD-1 refractory cancers, such as biliary tract cancer (BTC), remains elusive. We use multiplexed single-cell transcriptomic and epitope sequencing to profile greater than 200,000 peripheral blood mononuclear cells from advanced BTC patients (n = 9) and matched healthy donors (n = 8). Following anti-PD-1 treatment, CD14⁺ monocytes expressing high levels of immunosuppressive cytokines and chemotactic molecules (CD14_CTX) increase in the circulation of patients with BTC tumors that are CPI resistant. CD14_CTX can directly suppress CD4⁺ T cells and induce SOCS3 expression in CD4⁺ T cells, rendering them functionally unresponsive. The CD14_CTX gene signature associates with worse survival in patients with BTC as well as in other anti-PD-1 refractory cancers. These results demonstrate that monocytes arising after anti-PD-1 treatment can induce T cell paralysis as a distinct mode of tumor-mediated immunosuppression leading to CPI resistance.

Trial registration: ClinicalTrials.gov NCT02703714.

Keywords: CP: Cancer; biliary tract cancer; checkpoint inhibitors; cholangiocarcinoma; immunotherapy; monocytes; myeloid cells.

Publication types

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

MeSH terms

Biliary Tract Neoplasms* / drug therapy
Biliary Tract Neoplasms* / metabolism
Cytokines
Epitopes
Humans
Leukocytes, Mononuclear / metabolism
Monocytes* / metabolism
Paralysis
T-Lymphocytes / metabolism

Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis

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