The CLCF1-CNTFR axis drives an immunosuppressive tumor microenvironment and blockade enhances the effects of established cancer therapies.

Autor:	Sweet-Cordero E; University of California System., Marini K; Division of Oncology, Department of Pediatrics, University of California San Francisco., Champion E; Division of Oncology, Department of Pediatrics, University of California San Francisco., Lee A; University of California, San Francisco., Young I; Division of Oncology, Department of Pediatrics, University of California San Francisco., Leung S; Division of Oncology, Department of Pediatrics, University of California San Francisco., Mathey-Andrews N; Massachussets Institute of Technology., Jacks T; David H. Koch Institute for Integrative Cancer Research., Jackson P; Stanford University School of Medicine., Cochran J; Stanford University.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Mar 22. Date of Electronic Publication: 2024 Mar 22.
DOI:	10.21203/rs.3.rs-4046823/v1
Abstrakt:	Tumors comprise a complex ecosystem consisting of many cell types that communicate through secreted factors. Targeting these intercellular signaling networks remains an important challenge in cancer research. Cardiotrophin-like cytokine factor 1 (CLCF1) is an interleukin-6 (IL-6) family member secreted by cancer-associated fibroblasts (CAFs) that binds to ciliary neurotrophic factor receptor (CNTFR), promoting tumor growth in lung and liver cancer 1,2 . A high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1 has anti-oncogenic effects 3 . However, the role of CLCF1 in mediating cell-cell interactions in cancer has remained unclear. We demonstrate that eCNTFR-Fc has widespread effects on both tumor cells and the tumor microenvironment and can sensitize cancer cells to KRAS inhibitors or immune checkpoint blockade. After three weeks of treatment with eCNTFR-Fc, there is a shift from an immunosuppressive to an immunostimulatory macrophage phenotype as well as an increase in activated T, NKT, and NK cells. Combination of eCNTFR-Fc and αPD1 was significantly more effective than single-agent therapy in a syngeneic allograft model, and eCNTFR-Fc sensitizes tumor cells to αPD1 in a non-responsive GEM model of lung adenocarcinoma. These data suggest that combining eCNTFR-Fc with KRAS inhibition or with αPD1 is a novel therapeutic strategy for lung cancer and potentially other cancers in which these therapies have been used but to date with only modest effect. Overall, we demonstrate the potential of cancer therapies that target cytokines to alter the immune microenvironment. Competing Interests: Additional Declarations: Yes there is potential Competing Interest. E.A.S.C, and J.R.C are inventors on intellectual property related to this work that is owned by UCSF and Stanford University. J.R.C. is a cofounder and equity holder of Combangio, Inc. (now Kala Bio), xCella Biosciences (now OmniAb), Charged Biotherapeutics, TwoStep Therapeutics, and Red Tree Venture Capital; has financial interests in Aravive, Inc.; is a member of the Board of Directors of OmniAb, Revel Pharmaceuticals, Excellergy Therapeutics, Rondo Therapeutics, Tachyon Therapeutics, and Biograph 55; and is a Board Observer at Acrigen Biosciences.
Databáze:	MEDLINE
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