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.