SOX10 Loss Sensitizes Melanoma Cells to Cytokine-Mediated Inflammatory Cell Death

Author:

Rosenbaum Sheera R.1ORCID,Caksa Signe1ORCID,Stefanski Casey D.1ORCID,Trachtenberg Isabella V.1ORCID,Wilson Haley P.1ORCID,Wilski Nicole A.1ORCID,Ott Connor A.1ORCID,Purwin Timothy J.1ORCID,Haj Jelan I.1ORCID,Pomante Danielle1ORCID,Kotas Daniel1ORCID,Chervoneva Inna12ORCID,Capparelli Claudia34ORCID,Aplin Andrew E.14ORCID

Affiliation:

1. 1Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.

2. 2Division of Biostatistics, Thomas Jefferson University, Philadelphia, Pennsylvania.

3. 3Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.

4. 4Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Abstract

Abstract The transcription factor, SOX10, plays an important role in the differentiation of neural crest precursors to the melanocytic lineage. Malignant transformation of melanocytes leads to the development of melanoma, and SOX10 promotes melanoma cell proliferation and tumor formation. SOX10 expression in melanomas is heterogeneous, and loss of SOX10 causes a phenotypic switch toward an invasive, mesenchymal-like cell state and therapy resistance; hence, strategies to target SOX10-deficient cells are an active area of investigation. The impact of cell state and SOX10 expression on antitumor immunity is not well understood but will likely have important implications for immunotherapeutic interventions. To this end, we tested whether SOX10 status affects the response to CD8+ T cell–mediated killing and T cell–secreted cytokines, TNFα and IFNγ, which are critical effectors in the cytotoxic killing of cancer cells. We observed that genetic ablation of SOX10 rendered melanoma cells more sensitive to CD8+ T cell–mediated killing and cell death induction by either TNFα or IFNγ. Cytokine-mediated cell death in SOX10-deficient cells was associated with features of caspase-dependent pyroptosis, an inflammatory form of cell death that has the potential to increase immune responses. Implications: These data support a role for SOX10 expression altering the response to T cell–mediated cell death and contribute to a broader understanding of the interaction between immune cells and melanoma cells.

Funder

National Cancer Institute

Dr. Miriam and Sheldon G. Adelson Medical Research Foundation

American Cancer Society

Melanoma Research Foundation

Legacy of Hope

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology,Molecular Biology

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