Nature communications, 2022-01, Vol.13 (1), p.182-182, Article 182
2022
Details
- Autor(en) / Beteiligte
- Titel
- Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3Kα/β/δ treatment
- Ist Teil von
- Nature communications, 2022-01, Vol.13 (1), p.182-182, Article 182
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2022
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek - Freely accessible e-journals
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-021-27833-0Titel-ID: cdi_doaj_primary_oai_doaj_org_article_10d0bcbff27a44d084d7bcd464438339
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, Animals, Antibodies, Neutralizing - pharmacology, Antineoplastic Agents, Immunological - pharmacology, beta 2-Microglobulin - genetics, beta 2-Microglobulin - immunology, Castration, CD8 antigen, CD8-Positive T-Lymphocytes - drug effects, CD8-Positive T-Lymphocytes - immunology, CD8-Positive T-Lymphocytes - pathology, Cell Line, Tumor, Cell Movement - drug effects, Chemokine CCL5 - genetics, Chemokine CCL5 - immunology, Chemokine CXCL10 - genetics, Chemokine CXCL10 - immunology, Class I Phosphatidylinositol 3-Kinases - genetics, Class I Phosphatidylinositol 3-Kinases - immunology, CXCL10 protein, Disease Models, Animal, Drug Resistance, Neoplasm - drug effects, Drug Resistance, Neoplasm - genetics, Drug Resistance, Neoplasm - immunology, Gene Expression Regulation, Neoplastic, Humans, Immune checkpoint inhibitors, Immune Checkpoint Inhibitors - pharmacology, Immune system, Immunity, Immunosuppressive agents, Inflammation, Inhibitors, Interferon-alpha - genetics, Interferon-alpha - immunology, Interferon-gamma - genetics, Interferon-gamma - immunology, Lymphocytes, Lymphocytes T, Male, Mice, Mice, Knockout, PD-1 protein, Programmed Cell Death 1 Receptor - antagonists & inhibitors, Programmed Cell Death 1 Receptor - genetics, Programmed Cell Death 1 Receptor - immunology, Prostate - drug effects, Prostate - metabolism, Prostate - pathology, Prostate cancer, Prostatic Neoplasms, Castration-Resistant - drug therapy, Prostatic Neoplasms, Castration-Resistant - genetics, Prostatic Neoplasms, Castration-Resistant - metabolism, Prostatic Neoplasms, Castration-Resistant - pathology, PTEN Phosphohydrolase - deficiency, PTEN Phosphohydrolase - genetics, PTEN Phosphohydrolase - immunology, PTEN protein, Signal Transduction, Therapy, Tumor microenvironment, Tumor Microenvironment - drug effects, Tumor Microenvironment - genetics, Tumor Microenvironment - immunology, Tumors, α-Interferon, γ-Interferon