Cancer cell-derived type I interferons instruct tumor monocyte polarization
Dylan Kwart, Jing He, Subhashini Srivatsan, Clarissa Lett, Jacquelynn Golubov, Erin Oswald, Patrick Poon, Xuan Ye, Janelle Waite, Arielle Glatman Zaretsky, Sokol Haxhinasto, Elsa Au-Yeung, Namita T. Gupta, Joyce Chiu, Christina Adler, Samvitha Cherravuru, Evangelia Malahias, Nicole Negron, Kathryn Lanza, Angel Coppola, Min Ni, Hang Song, Yi Wei, Gurinder S. Atwal, Lynn E. Macdonald, Nicole Stokes Oristian, William Poueymirou, Vladimir Janković, Matthew G. Fury, Israel Lowy, Andrew Murphy, Matthew A. Sleeman, Bei Wang, Dimitris Skokos
Abstract
Monocytes are highly plastic immune cells that modulate antitumor immunity. Therefore, identifying factors that regulate tumor monocyte functions is critical for developing effective immunotherapies. Here, we determine that endogenous cancer cell-derived type I interferons (IFNs) control monocyte functional polarization. Guided by single-cell transcriptomic profiling of human and mouse tumors, we devise a strategy to distinguish and separate immunostimulatory from immunosuppressive tumor monocytes by surface CD88 and Sca-1 expression. Leveraging this approach, we show that cGAS-STING-regulated cancer cell-derived IFNs polarize immunostimulatory monocytes associated with anti-PD-1 immunotherapy response in mice. We also demonstrate that immunosuppressive monocytes convert into immunostimulatory monocytes upon cancer cell-intrinsic cGAS-STING activation. Consistently, we find that human cancer cells can produce type I IFNs that polarize monocytes, and our immunostimulatory monocyte gene signature is enriched in patient tumors that respond to anti-PD-1 immunotherapy. Our work exposes a role for cancer cell-derived IFNs in licensing monocyte functions that influence immunotherapy outcomes.