Journal
CELL REPORTS
Volume 40, Issue 12, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.111384
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Funding
- Merck
- Parker Institute for Cancer Immunotherapy
- Partner Therapeutics
- Prostate Cancer Foundation
- NIH [U01CA233100, R35CA253175, T32AI007334]
- American Society of Clinical Oncology Conquer Cancer Foundation
- Cholangiocarcinoma Foundation
- National Cancer Institute, National Institutes of Health [R21CA264381]
- UCSF Prostate Cancer Program 2021 Pilot Research Award
- Bili Project Foundation, Inc.
- Chan Zuckerberg Initiative
- Chan Zuckerberg Biohub
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Research has found that CD14+ monocytes increase in patients with anti-PD-1 refractory biliary tract cancer, leading to T cell dysfunction. The CD14CTX gene signature is associated with poorer prognosis.
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 multi-plexed 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 (CD14CTX) increase in the circulation of patients with BTC tumors that are CPI resistant. CD14CTX can directly suppress CD4+ T cells and induce SOCS3 expression in CD4+ T cells, rendering them functionally unresponsive. The CD14CTX 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.
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