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Prostate cancer is one of the leading causes of cancer death in men.
Currently, anti-androgen therapy is the main treatment method.
However, many patients will progress to castration-resistant prostate cancer and metastasize (CRPC)
.
There are currently no effective treatments for CRPC, including immunotherapy
.
On January 10, 2022, Nature Communications published online a research paper titled "Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3Kα/β/δ treatment" from Peking University Wu Hong's group
.
This study found that a novel PI3K inhibitor, BAY1082439, could improve the response of cancer cells to immune checkpoint blockade therapy by modulating the immunosuppressive pathway and tumor immune microenvironment in PTEN-deficient prostate cancer, providing clinical evidence for prostate cancer patients benefiting from immunotherapy.
previous basis
.
Abnormal activation of PI3K-AKT signaling pathway caused by PTEN deletion is the most common driver of prostate cancer
.
In 2018, Wu Hong's research group cooperated with Bayer and confirmed that BAY1082439, a novel PI3K inhibitor targeting three isoforms of α, β and δ at the same time, can inhibit the proliferation of cancer cells in Pten-deficient prostate cancer model mice
.
In the latest study, Wu Hong's group further found that intermittent administration of BAY1082439 could up-regulate cancer cell antigen presentation and T-cell chemokine expression by inhibiting the PI3K-regulated immunosuppressive pathway, and reduce T-regulatory cell-mediated tumorigenesis.
Exogenous immunosuppression, thereby increasing the infiltration and killing of tumors by CD8+ T cells, ensures the efficacy of subsequent anti-PD-1 immunotherapy
.
Intermittent BAY1082439 treatment converts "cold" tumors to "hot" tumors and promotes ICT therapy efficacy
.
Left: In PTEN-deficient prostate tumors, cancer cells upregulate the PI3K pathway and inhibit the IFN pathway, antigen presentation, and T-cell chemokine expression
.
At the same time, regulatory T cells in the tumor microenvironment inhibit the activation and proliferation of CD8+ T cells, resulting in a "cold" tumor state
.
Middle panel: Interval BAY1082439 treatment activates the IFN pathway in cancer cells and upregulates antigen presentation, while suppressing regulatory T cells in the tumor microenvironment
.
Dendritic cells that absorb cancer cell antigens migrate into intratumoral tertiary lymphoid structures (TLS), promoting CD8+ T cell activation and clonal proliferation
.
Clonally proliferating CD8+ T cells are attracted by T-cell chemokines expressed by tumor cells and infiltrate into tumors, transforming "cold" tumors into "hot" tumors
.
Infiltrating CD8+ T cells upregulate their own PD-1 expression and secrete IFNγ cytokines, which stimulate tumor cells to express PD-L1 and impair their immune activity
.
Right: Addition of anti-PD-1 antibody to BAY1082439-treated "hot tumors" can effectively promote T cell-mediated tumor killing.
Given that abnormal activation of the PI3K pathway is the most commonly upregulated signaling pathway in cancer, this study also has The application of PI3K inhibitor-targeted therapy and combined immunotherapy for other tumors provides preclinical evidence
.
Professor Wu Hong from the School of Life Sciences of Peking University and the Peking University-Tsinghua Joint Center for Life Sciences is the corresponding author of this article
.
Qi Zhi, a doctoral student of the PTN project in the School of Life Sciences of Peking University, is the first author; Xu Zihan, a doctoral student of the Li Cheng group of the School of Life Sciences, provided important bioinformatics support, Wu Hong’s group Zhang Liuzhen provided support for the mouse experiments, and Wu Hong Other researchers in the research group also participated
.
Liu Ningshu, a former Bayer researcher, also provided important guidance for the thesis
.
This research was supported by financial support from Peking University School of Life Sciences, Life Science Joint Center, Shenzhen Bay Laboratory Key Project and technical support from Peking University and Tsinghua University School of Life Sciences Instrument Center
.
Currently, anti-androgen therapy is the main treatment method.
However, many patients will progress to castration-resistant prostate cancer and metastasize (CRPC)
.
There are currently no effective treatments for CRPC, including immunotherapy
.
On January 10, 2022, Nature Communications published online a research paper titled "Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3Kα/β/δ treatment" from Peking University Wu Hong's group
.
This study found that a novel PI3K inhibitor, BAY1082439, could improve the response of cancer cells to immune checkpoint blockade therapy by modulating the immunosuppressive pathway and tumor immune microenvironment in PTEN-deficient prostate cancer, providing clinical evidence for prostate cancer patients benefiting from immunotherapy.
previous basis
.
Abnormal activation of PI3K-AKT signaling pathway caused by PTEN deletion is the most common driver of prostate cancer
.
In 2018, Wu Hong's research group cooperated with Bayer and confirmed that BAY1082439, a novel PI3K inhibitor targeting three isoforms of α, β and δ at the same time, can inhibit the proliferation of cancer cells in Pten-deficient prostate cancer model mice
.
In the latest study, Wu Hong's group further found that intermittent administration of BAY1082439 could up-regulate cancer cell antigen presentation and T-cell chemokine expression by inhibiting the PI3K-regulated immunosuppressive pathway, and reduce T-regulatory cell-mediated tumorigenesis.
Exogenous immunosuppression, thereby increasing the infiltration and killing of tumors by CD8+ T cells, ensures the efficacy of subsequent anti-PD-1 immunotherapy
.
Intermittent BAY1082439 treatment converts "cold" tumors to "hot" tumors and promotes ICT therapy efficacy
.
Left: In PTEN-deficient prostate tumors, cancer cells upregulate the PI3K pathway and inhibit the IFN pathway, antigen presentation, and T-cell chemokine expression
.
At the same time, regulatory T cells in the tumor microenvironment inhibit the activation and proliferation of CD8+ T cells, resulting in a "cold" tumor state
.
Middle panel: Interval BAY1082439 treatment activates the IFN pathway in cancer cells and upregulates antigen presentation, while suppressing regulatory T cells in the tumor microenvironment
.
Dendritic cells that absorb cancer cell antigens migrate into intratumoral tertiary lymphoid structures (TLS), promoting CD8+ T cell activation and clonal proliferation
.
Clonally proliferating CD8+ T cells are attracted by T-cell chemokines expressed by tumor cells and infiltrate into tumors, transforming "cold" tumors into "hot" tumors
.
Infiltrating CD8+ T cells upregulate their own PD-1 expression and secrete IFNγ cytokines, which stimulate tumor cells to express PD-L1 and impair their immune activity
.
Right: Addition of anti-PD-1 antibody to BAY1082439-treated "hot tumors" can effectively promote T cell-mediated tumor killing.
Given that abnormal activation of the PI3K pathway is the most commonly upregulated signaling pathway in cancer, this study also has The application of PI3K inhibitor-targeted therapy and combined immunotherapy for other tumors provides preclinical evidence
.
Professor Wu Hong from the School of Life Sciences of Peking University and the Peking University-Tsinghua Joint Center for Life Sciences is the corresponding author of this article
.
Qi Zhi, a doctoral student of the PTN project in the School of Life Sciences of Peking University, is the first author; Xu Zihan, a doctoral student of the Li Cheng group of the School of Life Sciences, provided important bioinformatics support, Wu Hong’s group Zhang Liuzhen provided support for the mouse experiments, and Wu Hong Other researchers in the research group also participated
.
Liu Ningshu, a former Bayer researcher, also provided important guidance for the thesis
.
This research was supported by financial support from Peking University School of Life Sciences, Life Science Joint Center, Shenzhen Bay Laboratory Key Project and technical support from Peking University and Tsinghua University School of Life Sciences Instrument Center
.
