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.


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 (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.

Trial registration: 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


  • Cytokines
  • Epitopes

Associated data