The RKIP-HER2 axis regulates breast cancer immune evasion

Introduction: Breast cancer (BC) is a prevalent malignancy worldwide among women. HER2 overexpression in a subset of BC (HER2+ BC) serves as a critical oncogenic driver and contributes to immune evasion. The Raf Kinase Inhibitor Protein (RKIP), a metastasis suppressor and an immune enhancer, is under-expressed in HER2+ BC. Treatment of HER2+ BC with anti-HER2 mAbs or chemical inhibitors has resulted in significant clinical responses in a subset of patients. However, acquired and induced resistance in HER2+ BC patients highlights the need for new effective therapies. Procedure: We have analyzed the signaling pathways mediated by both RKIP and HER2 and have found that RKIP and HER2 inductions and downstream signaling showed inverse cross-talks. Findings: The inverse cross-talks enabled us to establish a dysregulated RKIP-HER2 axis in HER2+ BC. The role of this dysregulated axis in immune evasion was examined. HER2 expression positively regulates immune evasion as it is involved in the expression of PD-L1, the polarization of TAMs, the infiltration of suppressor cells (Tregs, MDSCs), the inhibition of anti-tumor CD8T cells, and an overall immunosuppressive TME. In contrast, RKIP inhibits critical signaling pathways that regulate HER2 expression, including the Raf-MEK-ERK, NF-κB, and PI3K/Akt pathways, thereby preventing immune evasion. The inverse functional relationship between RKIP and HER2 was further supported by bioinformatic analyses that examined expressions and correlations by proteomics and survival analyses. Conclusion: Various therapeutic strategies are proposed aimed at targeting the dysregulated RKIP-HER2 axis in HER2+ BC to circumvent resistance and immune evasion.