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PI3Kβ controls immune evasion in PTEN-deficient breast tumors

ABSTRACT: Loss of the PTEN tumor suppressor is one of the most common oncogenic 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 the importance of PI3Kβ activity remain elusive. Using a syngeneic genetically-engineered mouse (GEM) model of invasive breast cancer driven by concurrent ablation of Pten and Trp53 (p53), we showed that genetic inactivation of PI3Kβ led to a robust anti-tumor immune response that abrogated tumor growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kβ inactivation in the PTEN-null setting led to reduced STAT3 signaling and increased expression of immune stimulatory molecules, thereby promoting anti-tumor immune responses. Pharmacological PI3Kβ inhibition also elicited anti-tumor immunity, and synergized with immunotherapy to inhibit tumor growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumors upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3Kβ controls immune escape in PTEN-null tumors, providing a rationale for combining PI3Kβ inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE225064 | GEO | 2023/03/07

REPOSITORIES: GEO

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Project description:The interaction of neoplastic cells with their tumor microenvironment (TME) is required for cancer progression. However, in vitro cancer models, including recent in vitro 3-dimensional (3D) organoid cultures of primary human tumors, are typically comprised exclusively of neoplastic epithelium, with stromal and/or immune interactions requiring artificial reconstitution. As relevant to cancer immunotherapy, the unified co-culture of primary tumor epithelia with their endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has remained particularly elusive. Here, we used a single 3D air-liquid interface (ALI) methodology to successfully propagate 3D Patient-Derived Tumor Organoids (PDOs) as primary tumor epithelia together with native immune and myofibroblast stromal compartments without reconstitution. Derived from >100 diverse human surgically resected tumor samples or from murine tumors in syngeneic immunocompetent mice, PDOs preserved cancer histologic subtypes and mutational spectrum with endogenous T, B, NK cells and macrophages integrally embedded amidst the tumor epithelium. PDO-based TILs accurately recapitulated the T cell receptor (TCR) spectrum of the original tumors, as determined by a robust droplet-based immune profiling solution that links gene expression and immune repertoire in single cells. Anti-PD-1 or anti-PD-L1 treatment of organoids from murine tumors from syngeneic immunocompetent hosts induced activation and cytolytic activity of tumor antigen-specific TILs, indicating successful PDO modeling of immune checkpoint blockade (ICB) and anti-tumor immunity. Crucially, the anti-PD-1 antibody nivolumab activated TILs in PDOs from human lung, renal and melanoma clinical tumor resections. The organoid-based propagation of primary tumor epithelium en bloc with its endogenous immune stroma should facilitate mechanistic investigation of TME-specific local tumor immunity, with applications for functional testing of individualized patient immunotherapy responses.

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PI3Kβ controls immune evasion in PTEN-deficient breast tumors

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