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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1470368
This article is part of the Research Topic The Influence of Cancer Cells, Tumor Microenvironment and their Crosstalk on Early Drug and Immunotherapy Developments View all articles

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

Provisionally accepted
Alf Spitschak Alf Spitschak 1Prabir Dhar Prabir Dhar 1Krishna P. Singh Krishna P. Singh 2Rosaely Casalegno Rosaely Casalegno 1Shailendra K. Gupta Shailendra K. Gupta 2Julio Vera González Julio Vera González 3,4Luca Musella Luca Musella 3,4Nico Murr Nico Murr 1Anja Stoll Anja Stoll 2Brigitte M. Pützer Prof. MD, PhD Brigitte M. Pützer Prof. MD, PhD 1*
  • 1 Institute of Experimental Gene Therapy and Cancer Research, University Medicine, Rostock, Germany
  • 2 Institute for Systems Biology and Bioinformatics, University of Rostock, Rostock, Mecklenburg-Vorpommern, Germany
  • 3 Laboratory of Systems Tumor Immunology, Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
  • 4 Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

The final, formatted version of the article will be published soon.

    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.

    Keywords: E2F1-STAT3/IL-6 network, melanoma secretome, Tumor Microenvironment, Immunomodulation, CD4 + /CD8 + T cells, Th2-Th1 shift, cancer metastasis, mathematical modeling

    Received: 25 Jul 2024; Accepted: 14 Oct 2024.

    Copyright: © 2024 Spitschak, Dhar, Singh, Casalegno, Gupta, Vera González, Musella, Murr, Stoll and Pützer Prof. MD, PhD. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Brigitte M. Pützer Prof. MD, PhD, Institute of Experimental Gene Therapy and Cancer Research, University Medicine, Rostock, Germany

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