Cancer cell-derived type I interferons instruct tumor monocyte polarization

• Published in: Cell reports (Cambridge) Vol. 41; no. 10; p. 111769
• Main Authors: Kwart, Dylan, He, Jing, Srivatsan, Subhashini, Lett, Clarissa, Golubov, Jacquelynn, Oswald, Erin M., Poon, Patrick, Ye, Xuan, Waite, Janelle, Zaretsky, Arielle Glatman, Haxhinasto, Sokol, Au-Yeung, Elsa, Gupta, Namita T., Chiu, Joyce, Adler, Christina, Cherravuru, Samvitha, Malahias, Evangelia, Negron, Nicole, Lanza, Kathryn, Coppola, Angel, Ni, Min, Song, Hang, Wei, Yi, Atwal, Gurinder S., Macdonald, Lynn, Oristian, Nicole Stokes, Poueymirou, William, Jankovic, Vladimir, Fury, Matthew, Lowy, Israel, Murphy, Andrew J., Sleeman, Matthew A., Wang, Bei, Skokos, Dimitris
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06-12-2022
• Subjects: Animals; cancer immunology; cGAS; Humans; immune checkpoint blockade; innate immunity; Interferon Type I; macrophages; MDSCs; Mice; Monocytes; Neoplasms; STING; tumor microenvironment; type I interferon; type I interferon; monocytes; MDSCs; macrophages; innate immunity; CP: Cancer; cancer immunology; cGAS; STING; tumor microenvironment; immune checkpoint blockade
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111769

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.
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•Immunostimulatory tumor monocytes (Tu.Mons) highly express type I IFN-stimulated genes•CD88/Sca-1 distinguish stimulatory “Tu.Mon1” from suppressive “Tu.Mon2” cells in mice•cGAS/STING-dependent cancer cell-derived type I IFNs drive Tu.Mon1 polarization•Tu.Mon1 polarization is associated with anti-PD-1 therapy response in mice and humans
The precise cues driving monocyte functional diversity in cancer remain unclear. Here, Kwart et al. demonstrate that cancer cell-derived type I interferons drive polarization of a phenotypically distinct subset of immunostimulatory tumor monocytes associated with response to anti-PD-1 immunotherapy.