Investigating the mechanism of ICB resistance in advanced biliary tract (BTC) cancer, Keenan et al. identified and tracked an inhibitory CD14+ monocyte population (CD14CTX) associated with poor response to anti-PD-1 therapy in peripheral blood, and corresponding CD14CTX signature-related TAMs in tumors (marked as SPP1+). The presence of the CD14CTX signature in tumors correlated with poor prognosis in multiple TCGA data sets and in anti-PD-1/L1-treated patients with melanoma and RCC. Purified CD14CTX cells or serum from BTC patients induced a previously described dysfunctional CD4+ SOCS3+ T cell population also observed in peripheral blood of patients with BTC.
Contributed by Ed Fritsch
ABSTRACT: Although suppressive myeloid cells have been proposed as a mechanism of resistance to immunotherapy, their role in response to checkpoint inhibitor treatment (CPI) in anti-PD-1 refractory cancers, such as biliary tract cancer (BTC), is largely unknown. We used multiplexed single-cell transcriptomic and epitope sequencing to profile >200,000 peripheral blood mononuclear cells from advanced BTC. In BTC patients, CD14+ monocytes expressing high levels of immunosuppressive cytokines and trafficking molecules involved in chemotaxis (CD14CTX) are associated with resistance to CPI. CD14CTX can directly suppress CD4+ T cells and induce SOCS3 expression in naive CD4+ T cells rendering them functionally unresponsive. Gene signatures from CD14CTX are correlated with worse survival in BTC patients as well as in other anti-PD-1 refractory cancers. These results demonstrate that monocytes arising in the setting of anti-PD-1 insensitivity can induce T cell paralysis as a distinct mode of tumor-mediated immunosuppression.
Author Info: (1) Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA(2) Cancer Immunotherapy Program, University of California, San Francisco, San F
Author Info: (1) Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA(2) Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA(3) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA(4) Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA(5) Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA(6) Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA(7) Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA(8) Department of Genome Sciences, University of Washington, Seattle, WA, USA(9) Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA(10) Chan Zuckerberg Biohub, San Francisco, CA, USA(11) J. David Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA(12) Center for Advanced Technologies, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco,
CA, USA(13) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA(14) Lead contact
