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A Phosphatidylinositol 3-Kinase Gamma Inhibitor Enhances Anti-Programmed Death-1/Programmed Death Ligand-1 Antitumor
Caixia Jiang1, Rongyu Liu1, Zhengyu Li1,2
1Department of Obstetrics and Gynecology West China Second University Hospital, Sichuan University Chengdu P. R. China.
Abstract:
Previous studies have shown that the effectiveness of immune checkpoint blockade in the treatment of ovarian cancer (OC) is poor. A promising small molecule inhibitor targeting phosphatidylinositol 3-kinase gamma (PI3Kγ) has recently been applied in combination with other drugs for tumor treatment. This study aimed to determine whether a PI3Kγ inhibitor can enhance the antitumor effects of anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1) therapies in OC and to explore the underlying immunomolecular mechanism involved. Changes in the expression of PI3Kγ, PD-1, PD-L1, and tumor-associated macrophages (TAMs) during the progression of OC were detected in clinical tissue samples. We also constructed a coculture system of OC cells with lymphocytes for in vitro study, and a subcutaneous and intraperitoneal implantation OC mouse model was constructed for in vivo studies. OC is an immunosuppressed tumor with predominant infiltration of M2 throughout the entire disease course. We also found that a PI3Kγ inhibitor combined with anti-PD-1 therapy can enhance the antitumor effects of anti-PD-1 agents by modulating the PI3Kγ-AKT-NF-κB pathway, reprogramming TAMs, decreasing the number of myeloid-derived suppressor cells, increasing the number of CD8+ T cells, and increasing the levels of proinflammatory factors; consequently, this approach transforms the tumor immune microenvironment of OC into a more active state.
Insights
Combining a PI3Kγ inhibitor with anti-PD-1 therapy shows promise for ovarian cancer (OC). This approach enhances anti-PD-1 effectiveness by reprogramming the tumor immune microenvironment, offering a new treatment strategy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Ovarian cancer (OC) exhibits poor response to immune checkpoint blockade therapies.
- Phosphatidylinositol 3-kinase gamma (PI3Kγ) inhibitors are emerging as potential therapeutic agents.
- Understanding the immunomolecular mechanisms in OC is crucial for improving treatment outcomes.
Purpose of the Study:
- To evaluate if a PI3Kγ inhibitor can augment the efficacy of anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1) therapies in ovarian cancer.
- To elucidate the underlying immunomolecular mechanisms by which PI3Kγ inhibition impacts the tumor immune microenvironment in OC.
Main Methods:
- Analysis of PI3Kγ, PD-1, PD-L1, and tumor-associated macrophages (TAMs) expression in clinical OC tissues.
- In vitro coculture systems of OC cells with lymphocytes.
- In vivo studies using subcutaneous and intraperitoneal OC mouse models.
Main Results:
- Ovarian cancer is characterized by an immunosuppressed tumor microenvironment with M2 macrophage infiltration.
- Combination therapy of a PI3Kγ inhibitor and anti-PD-1 significantly enhanced antitumor effects.
- The combination therapy modulated the PI3Kγ-AKT-NF-κB pathway, reprogrammed TAMs, reduced myeloid-derived suppressor cells, and increased CD8+ T cells and proinflammatory factors.
Conclusions:
- A PI3Kγ inhibitor combined with anti-PD-1 therapy can overcome resistance to anti-PD-1 agents in ovarian cancer.
- This combination strategy effectively reprograms the tumor immune microenvironment towards a more active, anti-tumor state.
- Targeting PI3Kγ offers a promising approach to enhance immunotherapy in ovarian cancer.
