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• W4310858866 abstract "•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 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. 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. Monocytes are a prominent population of circulating immunecells that respond to tissue-derived cues during inflammation.1Guilliams M. Mildner A. Yona S. Developmental and functional heterogeneity of monocytes.Immunity. 2018; 49: 595-613https://doi.org/10.1016/j.immuni.2018.10.005Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar,2Jakubzick C.V. Randolph G.J. Henson P.M. Monocyte differentiation and antigen-presenting functions.Nat. Rev. Immunol. 2017; 17: 349-362https://doi.org/10.1038/nri.2017.28Crossref PubMed Scopus (428) Google Scholar Depending on the context, monocytes become immunosuppressive or immunostimulatory, influencing neighboring immune cells like T lymphocytes in cancer.1Guilliams M. Mildner A. Yona S. Developmental and functional heterogeneity of monocytes.Immunity. 2018; 49: 595-613https://doi.org/10.1016/j.immuni.2018.10.005Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar,2Jakubzick C.V. Randolph G.J. Henson P.M. 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Sun J. Huang Y. Wang Y. Zhu Y.-J. Li Y.-J. Zhao W. Wei W.-X. et al.Blood lymphocyte-to-monocyte ratio identifies high-risk patients in diffuse large B-cell lymphoma treated with R-CHOP.PLoS One. 2012; 7: e41658https://doi.org/10.1371/journal.pone.0041658Crossref PubMed Scopus (121) Google Scholar,8Hu P. Shen H. Wang G. Zhang P. Liu Q. Du J. Prognostic significance of systemic inflammation-based lymphocyte- monocyte ratio in patients with lung cancer: based on a large cohort study.PLoS One. 2014; 9: e108062https://doi.org/10.1371/journal.pone.0108062Crossref PubMed Scopus (114) Google Scholar,9Eo W.K. Chang H.J. Kwon S.H. Koh S.B. Kim Y.O. Ji Y.I. Kim H.-B. Lee J.Y. Suh D.S. Kim K.H. et al.The lymphocyte-monocyte ratio predicts patient survival and aggressiveness of ovarian cancer.J. Cancer. 2016; 7: 289-296https://doi.org/10.7150/jca.13432Crossref PubMed Scopus (43) Google Scholar,10Wilcox R.A. Ristow K. Habermann T.M. Inwards D.J. Micallef I.N.M. Johnston P.B. Colgan J.P. 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In parallel, we confirmed that orthologous Tu.Mon populations exist in murine Lewis lung carcinoma (LLC) and colon adenocarcinoma clone 38 (MC38) syngeneic tumors. We show that adding the surface markers CD88 and Sca-1 to a flow cytometry profiling panel of well-defined myeloid lineage markers faithfully separates transcriptionally and functionally distinct Tu.Mon subsets, thereby enabling their examination in mouse models. Mechanistically, we found that cancer cell-intrinsic type I IFN production, regulated in a cGAS-STING-dependent manner without any exogenous trigger, controls immunostimulatory “Tu.Mon1” polarization. Preventing Tu.Mon1 polarization by blocking cancer cell IFN production results in accumulation of immunosuppressive “Tu.Mon2” monocytes and restrains anti-PD-1 treatment efficacy. On the other hand, enhancing Tu.Mon1 polarization by activating the cGAS-STING pathway in cancer cells reverses resistance to anti-PD-1 treatment in mouse models. By interrogating human clinical datasets, we validate that Tu.Mon1 polarization, defined by enrichment of a Tu.Mon1 gene signature, is associated with clinical response to anti-PD-1 immunotherapy. Overall, our data provide a framework for distinguishing Tu.Mon subsets and reveal a previously overlooked role for cancer cell-intrinsic type I IFN production in establishing an immunostimulatory subset of cancer-associated monocytes. To examine the molecular diversity of Tu.Mons, we profiled monocytes in lung adenocarcinoma (LUAD), a tumor highly infiltrated by monocytic cells.44Kim N. Kim H.K. Lee K. Hong Y. Cho J.H. Choi J.W. Lee J.-I. Suh Y.-L. Ku B.M. Eum H.H. et al.Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma.Nat. Commun. 2020; 11: 2285https://doi.org/10.1038/s41467-020-16164-1Crossref PubMed Scopus (238) Google Scholar,45He D. Wang D. Lu P. Yang N. Xue Z. Zhu X. Zhang P. Fan G. Single-cell RNA sequencing reveals heterogeneous tumor and immune cell populations in early-stage lung adenocarcinomas harboring EGFR mutations.Oncogene. 2021; 40: 355-368https://doi.org/10.1038/s41388-020-01528-0Crossref PubMed Scopus (52) Google Scholar,46Zilionis R. Engblom C. Pfirschke C. Savova V. Zemmour D. Saatcioglu H.D. Krishnan I. Maroni G. Meyerovitz C.V. Kerwin C.M. et al.Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species.Immunity. 2019; 50: 1317-1334.e10https://doi.org/10.1016/j.immuni.2019.03.009Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar We used a published scRNA-seq dataset of 11 LUAD tumors spanning early to advanced disease stages.44Kim N. Kim H.K. Lee K. Hong Y. Cho J.H. Choi J.W. Lee J.-I. Suh Y.-L. Ku B.M. Eum H.H. et al.Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma.Nat. Commun. 2020; 11: 2285https://doi.org/10.1038/s41467-020-16164-1Crossref PubMed Scopus (238) Google Scholar Of the 8,794 myeloid cells sequenced, we extracted 1,609 classical monocytic cells (Figures 1A and S1A–S1H). We selected cells that highly expressed CD14 and removed unrelated annotated cell types (Figures S1A and S1B). We also excluded monocyte-derived macrophages after performing unsupervised clustering analysis (Figures S1C–S1H). We confirmed that cells included in our final analysis were enriched with hallmark monocyte signature genes (Figures S1G and S1H). We identified three distinct subsets of human lung (hLung) Tu.Mons with unique cluster-specific differentially expressed genes (DEGs) (Figures 1A–1D, S1I, and S1J and Table S1). hLung Tu.Mon cluster C0 was marked by peripheral blood monocyte-associated genes (e.g., FCN1, S100A8, S100A9; Figure 1C), suggesting this cluster represents newly recruited Tu.Mons. Cluster C0 was also enriched with genes associated with inflammation and chemotaxis, including IL1B, THBS1, and VCAN (Figures 1C and 1D and Table S1). Cluster C2, the largest subset, was marked by expression of immunosuppressive myeloid cell genes like MRC1, STAB1, and DAB247Adamson S.E. Griffiths R. Moravec R. Senthivinayagam S. Montgomery G. Chen W. Han J. Sharma P.R. Mullins G.R. Gorski S.A. et al.Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation.J. Clin. Invest. 2016; 126: 1311-1322https://doi.org/10.1172/jci79590Crossref PubMed Scopus (0) Google Scholar,48Palani S. Elima K. Ekholm E. Jalkanen S. Salmi M. Monocyte stabilin-1 suppresses the activation of Th1 lymphocytes.J. Immunol. 2016; 196: 115-123https://doi.org/10.4049/jimmunol.1500257Crossref PubMed Scopus (30) Google Scholar (Figures 1C, 1D, and S1J). In addition, cluster C2 more highly expressed genes associated with resistance to ICB, including CCL18, SEPP1, FOLR2, NUPR1, and KLHDC8B,49Xiong D. Wang Y. You M. A gene expression signature of TREM2hi macrophages and γδ T cells predicts immunotherapy response.Nat. Commun. 2020; 11: 5084https://doi.org/10.1038/s41467-020-18546-xCrossref PubMed Scopus (38) Google Scholar as well as complement and lipoprotein metabolism-associated genes (C1QB, PLTP, APOE, and ABCA1; Figures 1C, 1D, and S1J and Table S1). Intriguingly, hLung Tu.Mon cluster C1 was uniquely defined by type I IFN-stimulated gene (ISG) expression, including ISG15, IFIT1, IFIT3, MX1, and LY6E (Figures 1C, 1D, and S1I and Table S1). Cluster C1 was also enriched with DEGs associated with processing and presentation of antigen to T cells (e.g., PSMB9, PSME2, PSMC1, B2M, CD86, and major histocompatibility complex (MHC) class I genes HLA-A and HLA-B), suggesting this Tu.Mon cluster may be immunostimulatory. To establish whether human Tu.Mon subsets exist in other tumor types, we analyzed monocytes from an scRNA-seq dataset with 23 colorectal cancer patients50Lee H.-O. Hong Y. Etlioglu H.E. Cho Y.B. Pomella V. Van den Bosch B. Vanhecke J. Verbandt S. Hong H. Min J.-W. et al.Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer.Nat. Genet. 2020; 52: 594-603https://doi.org/10.1038/s41588-020-0636-zCrossref PubMed Scopus (133) Google Scholar (Figures S1A and S1K–S1Q). We identified three Tu.Mon clusters in colorectal tumors (Figure S1L). Comparing hColon and hLung Tu.Mons, we found that hColon cluster C0 and hLung cluster C0 were strikingly similar and shared a significant number of DEGs (Figure S1R). Interestingly, hColon Tu.Mon clusters C1 and C2 were both enriched with hLung Tu.Mon cluster C1 genes (Figure S1R), suggesting that ISG-associated Tu.Mons may be enriched in some colorectal tumors. We next examined whether Tu.Mon subsets also exist in mouse tumors. We used the murine LLC lung and MC38 colon tumor models, which, like human LUAD and colorectal cancer, are both largely infiltrated by monocytic cells (Figures S2A–S2F). We established a flow cytometry gating strategy (CD45+CD11b+Siglec-F−Ly6G−Ly6Chigh) to distinguish Tu.Mons from other lymphoid and myeloid subsets (Figures S2G–S2M). To molecularly profile mouse Tu.Mons, we performed cellular indexing of transcriptomes and epitomes by sequencing" @default.
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• W4310858866 date "2022-12-01" @default.
• W4310858866 modified "2023-09-30" @default.
• W4310858866 title "Cancer cell-derived type I interferons instruct tumor monocyte polarization" @default.
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