Abstract

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (PI3K pathway) is a major intracellular regulatory pathway commonly involved in cancer survival, proliferation, migration, and metabolism. Activating mutations and amplifications of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) are frequent genomic features of head and neck squamous cell carcinoma (HNSCC). A growing body of evidence suggests that dysregulation of the PI3K pathway suppresses the anti-tumor immune response, thereby enabling tumor immune evasion. We retrospectively analyzed clinicopathologic and genomic data of patients with recurrent or metastatic (R/M) HNSCC treated with immune checkpoint inhibitors (ICI). PI3K pathway alterations were found in 44% and were associated with poor clinical outcomes in the human papillomavirus-negative (HPV-ve) HNSCC patients. PIK3CA expression was found to be inversely correlated with immune gene expression, decreased T-cell infiltration, and reduced CD8 T-cell cytotoxic activity. The pharmacologic inhibition of the PI3K pathway induced an increase in key immune-responsive gene expression in PIK3CA-mutant HPV-ve HNSCC cells. These findings suggest that the PI3K pathway activation promotes immune suppressive phenotype, and playing a role in conferring resistance to immune checkpoint inhibitors in HPV-ve subset of HNSCC patients. HighlightsAlterations in PI3K pathway are associated with poor clinical outcomes in HPV-negative HNSCC patients treated with immune checkpoint therapy. PI3K pathway activation correlates to immune suppressive tumor microenvironment in HNSCC. Pharmacologic inhibition of PI3K induces the expression of interferon-gamma responsive and antigen presentation machinery genes in HNSCC.