2. Academic Validation
  3. SOX10 Regulates Melanoma Immunogenicity through an IRF4-IRF1 Axis

SOX10 Regulates Melanoma Immunogenicity through an IRF4-IRF1 Axis

  • Cancer Res. 2021 Dec 15;81(24):6131-6141. doi: 10.1158/0008-5472.CAN-21-2078.
Satoru Yokoyama 1,  Atsushi Takahashi 2,  Ryota Kikuchi 2,  Soshi Nishibu 2,  Jennifer A Lo 3,  Miroslav Hejna 4,  Wooyoung M Moon 4,  Shinichiro Kato 3 5 6,  Yue Zhou 2,  F Stephen Hodi 7,  Jun S Song 4,  Hiroaki Sakurai 2,  David E Fisher 3,  Yoshihiro Hayakawa 5
Affiliations

Affiliations

  • 1 Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan. yokoyama@pha.u-toyama.ac.jp.
  • 2 Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
  • 3 Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • 4 Department of Physics, University of Illinois, Urbana-Champaign, Urbana, Illinois.
  • 5 Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
  • 6 Department of Immunology, Center for 5D Cell Dynamics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
PMID: 34728538 DOI: 10.1158/0008-5472.CAN-21-2078
Abstract

Loss-of-function mutations of JAK1/2 impair Cancer cell responsiveness to IFNγ and immunogenicity. Therefore, an understanding of compensatory pathways to activate IFNγ signaling in Cancer cells is clinically important for the success of immunotherapy. Here we demonstrate that the transcription factor SOX10 hinders immunogenicity of melanoma cells through the IRF4-IRF1 axis. Genetic and pharmacologic approaches revealed that SOX10 repressed IRF1 transcription via direct induction of a negative regulator, IRF4. The SOX10-IRF4-IRF1 axis regulated PD-L1 expression independently of JAK-STAT pathway activity, and suppression of SOX10 increased the efficacy of combination therapy with an anti-PD-1 antibody and histone deacetylase inhibitor against a clinically relevant melanoma model. Thus, the SOX10-IRF4-IRF1 axis serves as a potential target that can bypass JAK-STAT signaling to immunologically warm up melanoma with a "cold" tumor immune microenvironment. SIGNIFICANCE: This study identifies a novel SOX10/IRF4 pathway that regulates noncanonical induction of IRF1 independent of the JAK-STAT pathway and can be targeted to improve the efficacy of anti-PD-1 therapy in melanoma.

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