Johann S. Bergholz*, Qiwei Wang*, Qi Wang*, Michelle Ramseier, Sanjay Prakadan, Weihua Wang, Rong Fang, Sheheryar Kabraji, Qiang Zhou, G. Kenneth Gray, Kayley Abell-Hart, Shaozhen Xie, Xiaocan Guo, Hao Gu, Thanh Von, Tao Jiang, Shuang Tang, Gordon Freeman, Hye-Jung Kim, Alex K. Shalek, Thomas M. Roberts, Jean J. Zhao

Loss of the PTEN tumor suppressor is one of the most common cancer drivers across all cancer types. PTEN is the major negative regulator of phosphoinositide-3 kinase (PI3K) signaling. Notably, the PI3Kβ isoform has been shown to play an important role in PTEN-deficient tumors, but the mechanisms underlying this phenomenon remain elusive. Using a syngeneic genetically engineered mouse (GEM) model of invasive breast tumor driven by concurrent ablation of Pten and Trp53 (p53), we showed that genetic inactivation of PI3Kβ abrogated tumor growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kβ inactivation in the PTEN-null setting down-regulated STAT3 signaling in tumor cells, thus relieving suppression of immune stimulatory cytokines and pathways, and thereby promoting robust anti-tumor immune responses in the tumor microenvironment (TME). Pharmacological PI3Kβ inhibition on established PTEN-null tumors also elicited anti-tumor immunity in tumor cells and the TME, and synergized with immunotherapy to inhibit tumor growth. Mice rendered tumor-free also displayed memory immunity, evidenced by the ability to reject tumors upon re-challenge. Together, our findings suggest that PI3Kβ controls immune escape in PTEN-null tumors, thereby providing a rationale for combining PI3Kβ inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.

scRNA-seq data characterized the immune infiltrates of three GEM models with differing isoform-specific PI3K genetic ablation: PPA (PI3Kα), PPB (PI3Kβ), and PP (no PI3K ablation). We find that the immune infiltrate of PPB tumors are characterized by interferon-responsive T cells and monocytes, in contrast to increased representation of M2-like myeloid cells in PP and PPA tumor immune infiltrates.