GSTA4 Governs Melanoma Immune Resistance and Metastasis

Abstract

Abstract Among factors involved in cancer cells escaping from immune responses, an intrinsic defect in the IFNγ response is considered to be one of the major players allowing cancer cells to evade the host immunity. In this study, we investigated how tumor cells escape from the IFNγ-dependent immune response through the immunoediting process by analyzing originally established immune-escape variants of melanoma cells. We found that the immune-escape melanoma variants gained resistance to the IFNγ-induced oxidative stress response and identified glutathione-S-transferase-4 (GSTA4) as a critical molecule in this process. Furthermore, the immune escape melanoma variants acquired a greater metastatic ability by a GSTA4-dependent mechanism. Implications: Considering the importance of GSTA4 in controlling IFNγ responsiveness and the metastatic potential of other melanoma cells, our results highlight a novel mechanism whereby cancer cells escape from host immunity and gain metastatic ability by acquiring resistance to oxidative stress responses through the upregulation of GSTA4.