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

• Published in: Cell reports (Cambridge) 2022-09, Vol.40 (12), p.111384-111384, Article 111384
• Main Authors: Keenan, Bridget P., McCarthy, Elizabeth E., Ilano, Arielle, Yang, Hai, Zhang, Li, Allaire, Kathryn, Fan, Zenghua, Li, Tony, Lee, David S., Sun, Yang, Cheung, Alexander, Luong, Diamond, Chang, Hewitt, Chen, Brandon, Marquez, Jaqueline, Sheldon, Brenna, Kelley, Robin K., Ye, Chun Jimmie, Fong, Lawrence
• Format: Article
• Language: English
• Subjects: biliary tract cancer; Biliary Tract Neoplasms - drug therapy; Biliary Tract Neoplasms - metabolism; checkpoint inhibitors; cholangiocarcinoma; Cytokines; Epitopes; Humans; immunotherapy; Leukocytes, Mononuclear - metabolism; monocytes; Monocytes - metabolism; myeloid cells; Paralysis; T-Lymphocytes - metabolism
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •Multi-omic single-cell sequencing reveals circulating myeloid states in biliary cancer•The CD14CTX monocyte state is associated with resistance to checkpoint inhibitors (CPI)•The CD14CTX molecular signature associates with poor prognosis across cancer types•CD14CTX induce CD4+ T cell immune paralysis, a potential mechanism of CPI resistance Keenan et al. report that a monocyte population expressing immunosuppressive chemokines and cytokines (CD14CTX) is induced with anti-PD-1 and associates with resistance to treatment in biliary tract cancer. CD14CTX induce immune-paralyzed CD4+ T cells, representing an alternative mechanism of resistance in checkpoint inhibitor-refractory cancers.