Abstract 6861: PIK3CA activating mutation promotes an immune suppressive microenvironment in squamous cell carcinoma

Abstract Head and neck squamous cell carcinoma (HNSCC) is a leader in cancer incidence worldwide. Recently, immunotherapies such as immune checkpoint blockade (ICB) have offered great promise in treating many solid tumors, including HNSCCs, that are refractory to chemotherapy and radiation. Challengingly, HNSCC patients often relapse following ICB treatment due to the lack of a thorough 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 imperative to grasp the mechanisms of cancer immune evasion in individuals with specific genetic profiles to enhance the precision of immunotherapy. Cancer immune evasion has emerged as a hallmark of cancer and is facilitated by a highly complex tumor microenvironment (TME). 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. Additionally, our data supports that the tumor interstitial fluid (TIF) of PIK3CA mutant SCC tumors can enhance the suppressive activity of MDSCs on cytotoxic T cells. These results suggest that the acquisition of PIK3CA mutation may trigger TICs to release additional factors to further modify MDSC activities. A critical method by which MDSCs suppress T cells is through the production and respiratory burst of reactive oxygen species (ROS). RNA sequencing revealed that PIK3CA mutant SCCs have multiple mechanisms of increasing ROS in the TME and specifically in MDSCs, while simultaneously upregulating lipid metabolism genes, such as SCD1, to protect itself from MDSC-derived ROS. This study reveals a potential strategy for targeting PIK3CA mutant SCCs as a promising precision immunotherapy to enhance the efficacy of ICB treatments. Citation Format: Benjamin T. Nicholson, Weijie Guo, Yuxuan Miao. PIK3CA activating mutation promotes an immune suppressive microenvironment in squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6861.