A SOX9-B7x axis safeguards dedifferentiated tumor cells from immune surveillance to drive breast cancer progression.

Autor:	Liu Y; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., John P; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Nishitani K; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Cui J; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Nishimura CD; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Christin JR; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Couturier N; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Ren X; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Wei Y; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Pulanco MC; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Galbo PM Jr; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Zhang X; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Fu W; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Cui W; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Bartholdy BA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Zheng D; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Lauvau G; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Fineberg SA; Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA., Oktay MH; Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Gruss-Lipper Biophotonic Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Zang X; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Urology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: xingxing.zang@einsteinmed.edu., Guo W; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: wenjun.guo@einsteinmed.edu.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2023 Dec 04; Vol. 58 (23), pp. 2700-2717.e12. Date of Electronic Publication: 2023 Nov 13.
DOI:	10.1016/j.devcel.2023.10.010
Abstrakt:	How dedifferentiated stem-like tumor cells evade immunosurveillance remains poorly understood. We show that the lineage-plasticity regulator SOX9, which is upregulated in dedifferentiated tumor cells, limits the number of infiltrating T lymphocytes in premalignant lesions of mouse basal-like breast cancer. SOX9-mediated immunosuppression is required for the progression of in situ tumors to invasive carcinoma. SOX9 induces the expression of immune checkpoint B7x/B7-H4 through STAT3 activation and direct transcriptional regulation. B7x is upregulated in dedifferentiated tumor cells and protects them from immunosurveillance. B7x also protects mammary gland regeneration in immunocompetent mice. In advanced tumors, B7x targeting inhibits tumor growth and overcomes resistance to anti-PD-L1 immunotherapy. In human breast cancer, SOX9 and B7x expression are correlated and associated with reduced CD8 + T cell infiltration. This study, using mouse models, cell lines, and patient samples, identifies a dedifferentiation-associated immunosuppression mechanism and demonstrates the therapeutic potential of targeting the SOX9-B7x pathway in basal-like breast cancer. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu