Oncogenic PIK3CA recruits myeloid‐derived suppressor cells to shape the immunosuppressive tumour microenvironment in luminal breast cancer through the 5‐lipoxygenase‐dependent arachidonic acid pathway

Background: Oncogenic PIK3CA mutations (PIK3CA(mut)) frequently occur in a higher proportion in luminal breast cancer (LBC), especially in refractory advanced cases, and are associated with changes in tumour cellular metabolism. Nevertheless, its effect on the progression of the immune microenvironment (TIME) within tumours and vital molecular events remains veiled. Methods: Multiplex immunohistochemistry (mIHC) and single‐cell mass cytometry (CyTOF) was used to describe the landscape of TIME in PIK3CA(mut) LBC. The PIK3CA mutant cell lines were established using CRISPER/Cas9 system. The gene expression levels, protein secretion and activity of signaling pathways were measured by real‐time RT‐PCR, ELISA, immunofluorescence staining or western blotting. GSEA analysis, transwell chemotaxis assay, live cell imaging, flow cytometry metabolite analysis targeting arachidonic acid, Dual‐luciferase reporter assay, and Chromatin immunoprecipitation assay were used to investigate the underlying function and mechanism of the PI3K/5‐LOX/LTB4 axis. Results: PIK3CA(mut) LBC cells can induce an immunosuppressive TIME by recruiting myeloid‐derived suppressor cells (MDSCs) and excluding cytotoxic T cells via the arachidonic acid (AA) metabolism pathway. Mechanistically, PIK3CA(mut) activates the transcription of 5‐lipoxygenase (5‐LOX) in a STAT3‐dependent manner, which in turn directly results in high LTB4 production, binding to BLT2 on MDSCs and promoting their infiltration. Since a suppressive TIME is a critical barrier for the success of cancer immunotherapy, the strategies that can convert “cold” tumours into “hot” tumours were compared. Targeted therapy against the PI3K/5‐LOX/LTB4 axis synergizing with immune checkpoint blockade (ICB) therapy achieved dramatic shrinkage in vivo. Conclusions: The results emphasize that PIK3CA(mut) can induce immune evasion by recruiting MDSCs through the 5‐LOX‐dependent AA pathway, and combination targeted therapy with ICB may provide a promising treatment option for refractory advanced LBC patients.