E2F1-induced autocrine IL-6 inflammatory loop mediates cancer-immune crosstalk that predicts T cell phenotype switching and therapeutic responsiveness.

Autor:	Spitschak A; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany., Dhar P; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany., Singh KP; Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany., Garduño RC; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany., Gupta SK; Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.; Department of Biomedical Engineering & Bioinformatics, Chhattisgarh Swami Vivekananda Technical University, Bhilai, Chhattisgarh, India., Vera J; Laboratory of Systems Tumor Immunology, Department of Dermatology, Uniklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany., Musella L; Laboratory of Systems Tumor Immunology, Department of Dermatology, Uniklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany., Murr N; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany., Stoll A; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany., Pützer BM; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.; Department Life, Light & Matter, University of Rostock, Rostock, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Oct 31; Vol. 15, pp. 1470368. Date of Electronic Publication: 2024 Oct 31 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1470368
Abstrakt:	Melanoma is a metastatic, drug-refractory cancer with the ability to evade immunosurveillance. Cancer immune evasion involves interaction between tumor intrinsic properties and the microenvironment. The transcription factor E2F1 is a key driver of tumor evolution and metastasis. To explore E2F1's role in immune regulation in presence of aggressive melanoma cells, we established a coculture system and utilized transcriptome and cytokine arrays combined with bioinformatics and structural modeling. We identified an E2F1-dependent gene regulatory network with IL6 as a central hub. E2F1-induced IL-6 secretion unleashes an autocrine inflammatory feedback loop driving invasiveness and epithelial-to-mesenchymal transition. IL-6-activated STAT3 physically interacts with E2F1 and cooperatively enhances IL-6 expression by binding to an E2F1-STAT3-responsive promoter element. The E2F1-STAT3/IL-6 axis strongly modulates the immune niche and generates a crosstalk with CD4 + cells resulting in transcriptional changes of immunoregulatory genes in melanoma and immune cells that is indicative of an inflammatory and immunosuppressive environment. Clinical data from TCGA demonstrated that elevated E2F1, STAT3, and IL-6 correlate with infiltration of Th2, while simultaneously blocking Th1 in primary and metastatic melanomas. Strikingly, E2F1 depletion reduces the secretion of typical type-2 cytokines thereby launching a Th2-to-Th1 phenotype shift towards an antitumor immune response. The impact of activated E2F1-STAT3/IL-6 axis on melanoma-immune cell communication and its prognostic/therapeutic value was validated by mathematical modeling. This study addresses important molecular aspects of the tumor-associated microenvironment in modulating immune responses, and will contribute significantly to the improvement of future cancer therapies. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Spitschak, Dhar, Singh, Garduño, Gupta, Vera, Musella, Murr, Stoll and Pützer.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu