Abstract LB243: Secreted PTEN-long downregulates PI3K signaling and PD-L1 and promotes anti-tumor antigen-presenting cell functions to cause regressions of mouse tumors

Abstract PTEN is well known as a tumor suppressor that inhibits the PI3K/AKT pathway, but the role of its secreted isoform PTEN-Long (PTEN-L) is not fully understood. We developed tools to study PTEN-L independent of PTEN using cancer cell lines engineered to express PTEN-L, a mouse engineered to overexpress Pten-L, and Adeno-Associated Virus (AAV)-Pten-L treated xenograft models. AAV-Pten-L was engineered to be expressed in the liver, where it was efficiently secreted into blood using a strong signal peptide for the liver. Beyond its known ability to inhibit PI3K/AKT signaling, we showed that Pten-L entered tumor cells and macrophages and altered interferon-γ and TGF-β signaling as well as immune cell composition, which triggered the rapid regression of small mouse tumors. Pten-L treatment activated immune cells in the tumor microenvironment, including macrophages, T cells, and NK cells. These changes were associated with enhanced MHC-II and CD80 expression by macrophages and reduced expression of PD-L1 by tumor cells and macrophages. Depletion experiments using anti-CD8 or anti-CD80 antibodies revealed that CD8+ T-cells and antigen-presenting macrophage cells were required for AAV-Pten-L-induced tumor regression. These results demonstrate the capacity of secreted Pten-L to stimulate the innate immune system and attenuate the immune checkpoint ligand PD-L1 in the tumor, which likely together orchestrate an adaptive immune response to inhibit the growth of established tumors. The first and second authors are co-first authors. Citation Format: Jia Xu, Tiphaine Martin, Daniel Lozano-Ojalvo, Andrew Baik, Bruno Giotti, Ashikur Rahaman, Andrew L. Wolfe, Natalie Suhy, Royce Zhou, Zhengxiang He, Kaitlyn Bosch, Madhuri Kalathur, Elias Stratikopoulos, Shen Yao, Ruifang Qiao, Sergio Lira, Emily Gallagher, Joshua Brody, Jordi Ochando, Alexander Tsankov, Katherine Cygnar, Aris Economides, Ramon E. Parsons. Secreted PTEN-long downregulates PI3K signaling and PD-L1 and promotes anti-tumor antigen-presenting cell functions to cause regressions of mouse tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB243.