Elevated Transglutaminase-2 in SOX10-Deficient Melanoma Promotes Tumor Onset and Decreases Intratumoral CD4+ T Cells

Melanoma heterogeneity contributes to therapy resistance and immune evasion. The loss of SOX10, a neural crest lineage-specific transcription factor, leads to phenotypic switching from a proliferative cell state to an invasive, drug-tolerant cell state. SOX10-deficient cells are able to persist during immunotherapy treatment, highlighting the need to characterize the factors that regulate immune evasion downstream of SOX10 loss. Here, we found that SOX10-deficient melanoma cell lines and patient samples express elevated levels of TGM2, a transglutaminase family member. TGM2 upregulation in SOX10 knockout cells was reversed by inhibition of epigenetic reader BET proteins. Knockdown of TGM2 did not affect the SOX10-deficient invasive cell state; however, overexpression of TGM2 in syngeneic melanomas promoted tumor onset in immunocompetent mice, but not in immunodeficient mice, suggesting an immune-mediated effect. TGM2 overexpression in melanoma was associated with decreased intratumoral CD4+ T cells, and depletion of CD4+ T cells abolished the tumor-promoting effect of TGM2. These data indicate that TGM2 is negatively regulated by SOX10 in melanoma and can promote an immunosuppressive tumor microenvironment.