PIK3CA activating mutation reshapes the tumor microenvironment to promote immune evasion in squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a leader in cancer incidence worldwide. Although the introduction of immunotherapy, such as immune checkpoint blockade (ICB), has improved the landscape of cancer treatment in many solid tumors, including HNSCCs, there remain challenges in achieving durable responses with such therapies. Indeed, HNSCC patients often relapse following ICB treatment. While relapse events are high, there is a lack of understanding of the mechanisms underlying cancer immune evasion. These disparities in patient outcomes strongly suggest the existence of genetic variations that underlie their distinct responses to ICB. Although the specific oncogenic mutations responsible for driving relapse in SCC patients remain unclear, it is critical to elucidate the mechanisms of cancer immune evasion in individuals with specific genetic profiles to enhance the precision of immunotherapy. We aim to understand the genetic basis shaping the immune suppressive TME and hypothesize that oncogenic driver mutations play a dominant role in preventing the immune clearance of transformed cells by reprogramming the immune landscape in the tumors. To determine the critical genetic signatures enriched in SCC patients that can impact anti-tumor immunity, we analyzed TCGA data which revealed a strong negative correlation between PIK3CA level and CD8+ T cell signatures. We have identified that activating mutations in the PIK3CA gene, found in 20% of HNSCCs, promote rapid tumor relapse after initial response to anti-PD-L1 and anti-CTLA-4 ICB treatments. Utilizing single-cell analysis, quantitative immune profiling, and multiplexed imaging, our lab showed that tumor-initiating cells (TICs) in SCCs can have an intricate dialogue with myeloid-derived suppressor cells (MDSCs) where TICs secrete factors to enhance MDSC recruitment and suppressive function on cytotoxic T cells. Our lab also identified that SOX2 amplification in PIK3CA mutant SCC could modulate neutrophils and block their interferon responses via activation of fatty acid desaturase 1 (FADS1) to aid neutrophils in maintaining their immune suppressive functions during immunotherapy treatments. As such, this study has led to key mechanistic understanding of how PIK3CA mutation allows cancer cells to shape the immune suppressive responses. Thus, our findings uncover a unique mechanism whereby PIK3CA mutant SCCs critically shape the tumor microenvironment to survive robust immunotherapy and give rise to tumor relapse.