Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3Kα/β/δ treatment

Zhi Qi, Zihan Xu, Liuzhen Zhang, Yongkang Zou, Jinping Li, Wenyu Yan, Cheng Li, Ningshu Liu and Hong Wu ()
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Zhi Qi: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University
Zihan Xu: School of Life Sciences, Peking University
Liuzhen Zhang: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University
Yongkang Zou: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University
Jinping Li: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University
Wenyu Yan: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University
Cheng Li: School of Life Sciences, Peking University
Ningshu Liu: Bayer AG, Drug Discovery TRG Oncology
Hong Wu: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Combining immune checkpoint therapy (ICT) and targeted therapy holds great promises for broad and long-lasting anti-cancer therapies. However, combining ICT with anti-PI3K inhibitors have been challenging because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we find that intermittent but not daily dosing of a PI3Kα/β/δ inhibitor, BAY1082439, on Pten-null prostate cancer models could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNα/IFNγ pathway activation, β2-microglubin expression and CXCL10/CCL5 secretion. With its preferential regulatory T cell inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells, most likely via tertiary lymphoid structures. Once primed, tumors remain T cell-inflamed, become responsive to anti-PD-1 therapy and have durable therapeutic effect. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn “cold” tumors into T cell-inflamed ones, paving the way for successful ICT.

Date: 2022
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DOI: 10.1038/s41467-021-27833-0

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