SLC7A2-mediated lysine catabolism inhibits immunosuppression in triple negative breast cancer

Abstract

Breast cancer is one of the most common malignancy worldwide. SLC7A2 is abnormally expressed in multi-type cancers. However, the potentials of SLC7A2 in tripe negative breast cancer (TNBC) are still unclear. This study aimed to investigate the roles of SLC7A2 and the underlying molecular mechanisms. mRNA expression was detected by RT-qPCR. The release of cytokines was detected using ELISA. Protein expression was detected by western blot. Histone crotonylation was performed using in vitro histone crotonylation assay. functional analysis was performed using CCCK-8 and flow cytometry assay. Xenografting assay was conducted to further verify the roles of SLC7A2 in TNBC. The expression of CD8A was detected using immunohistochemistry. SLC7A2 was downregulated in TNBC tumors. Low levels of SLC7A2 were associated with advanced stages and lymph node metastasis. SLC7A2 expression was positive correlated with CD8A. SLC7A2-mediated lysine catabolism drove the activation of CD8+ T cells. Moreover, SLC7A2 promoted the histone crotonylationvia upregulating ACOX1 and downregulated CDYL. SLC7A2 promoted the interaction between ACOX1 and TCF1, resulting the proliferation of CD8+ T cells. Additionally, overexpression of SLC7A2 activated CD8+ T cells and enhanced the chemosensitivity of anti-PD-1 therapies in vivo. SLC7A2 may function as an anti-tumor gene in TNBC via activating anti-tumor immunity. Therefore, SLC7A2/ ACOX1/TCF1 signaling may be promising strategy for TNBC.