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

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

  • Nat Commun. 2022 Jan 10;13(1):182. doi: 10.1038/s41467-021-27833-0.
Zhi Qi 1 2 3,  Zihan Xu 2,  Liuzhen Zhang 1 2 3,  Yongkang Zou 1 2 3 4,  Jinping Li 1 2 3,  Wenyu Yan 1 2 3,  Cheng Li 2,  Ningshu Liu 5 6,  Hong Wu 7 8 9 10
Affiliations

Affiliations

  • 1 The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China.
  • 2 School of Life Sciences, Peking University, Beijing, China.
  • 3 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
  • 4 Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China.
  • 5 Bayer AG, Drug Discovery TRG Oncology, Muellerstrasse 178, 13353, Berlin, Germany.
  • 6 Hehlius Biotech, Inc., 1801 Hongmei Rd, Shanghai, 200233, China.
  • 7 The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China. hongwu@pku.edu.cn.
  • 8 School of Life Sciences, Peking University, Beijing, China. hongwu@pku.edu.cn.
  • 9 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China. hongwu@pku.edu.cn.
  • 10 Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China. hongwu@pku.edu.cn.
PMID: 35013322 DOI: 10.1038/s41467-021-27833-0
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.

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