ABSTRACT There is a critical need to develop novel therapies for head and neck squamous cell carcinoma (HNSCC). The incidence of HPV-related HNSCC is rapidly rising in the United States and other countries around the world, while tobacco-related HNSCC remains an aggressive disease with poor prognosis and limited therapeutic options. Worldwide, HNSCC accounts for over 600,000 cases annually and is a leading cause of cancer mortality in developing countries. A majority of HNSCC patients present initially with locally or locoregionally advanced disease, yet these patients largely succumb to locally recurrent disease. Gene expression profiling and modeling strongly support a critical role for inflammation in HNSCC initiation and progression. Immune therapy holds promise for the treatment of HNSCC, as the immunotherapeutic agent nivolumab (anti-PD-1) recently demonstrated clinical activity in a small percentage of patients with recurrent/metastatic HNSCC. However, these findings suggest that HNSCC patients would be excellent candidates for novel immune therapeutics that could target resistance to anti-PD-1. We have found that PI3Kγ in immune suppressive Tumor Associated Macrophages (TAMs) promotes tumor immune suppression and resistance to checkpoint inhibitors in mouse models of HNSCC. Genetic or pharmacological inactivation of PI3Kγ, but not of other PI3K isoforms, repolarized TAMs toward a pro-inflammatory, anti-tumor phenotype and synergized with checkpoint inhibitors to activate memory T cells and eradicate HNSCC tumors. Our studies indicate that PI3Kγ inhibitors, such as the investigational agent IPI-549, may be valuable immune oncologic agents to treat and monitor HNSCC patient outcomes. Our studies also identified a novel PI3Kγ-driven signature of immune suppression - that predicts decreased survival in HNSCC patients. We propose to test the hypothesis that this PI3Kγ- mediated signature of immune suppression can be used to monitor therapeutic responses to PI3Kγ inhibitors. We will also test the hypothesis that therapeutic strategies that block PI3Kγ-mediated immune suppression will synergize with T cell targeted therapeutics to improve outcomes in HNSCC patients. The specific aims of this proposal are 1) To Identify the mechanisms by which PI3Kγ inhibitors synergize with anti-PD-1 to promote T cell recruitment and activation in vivo, using mouse models of HPV+ and HPV- carcinogen-induced HNSCC, 2) To determine the effect of the PI3Kγ inhibitor IPI-549 on tumor immune responses in patients with resectable HNSCC, 3) To evaluate biomarkers of immune response in recurrent/metastatic HNSCC patients treated with IPI-549 in combin...