219P - Radiotherapy, in conjunction with a PI3Kd/? inhibitor, enhances effector CD8+ T cell-mediated anti-tumor immune responses and the memory function of T cells within the tumor microenvironment by stimulating innate immunity

Background

Retrospective investigations indicate that inhibiting PI3Kδ and/or γ, which are prevalent in leukocytes, elicits an anticancer immune response by reducing the activity of immunosuppressive cells. However, the isolated inhibition of either PI3Kδ or γ is insufficient for the complete eradication of solid tumors.

Methods

We utilized BR101801, a PI3Kδ/γ inhibitor, in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor. BR101801 was delivered on a daily basis, and the target tumor region received localized irradiation. We consistently observed tumor growth and assessed immunological alterations via flow cytometry, ELISpot, and transcriptional analysis. Furthermore, we examined the mechanism of anticancer immunological effects via BR drug and radiation therapy by inhibiting the pathway using antibody treatment.

Results

Together with irradiation, BR101801 reduced Treg proliferation and increased tumor-specific CD8α+ T cells in the tumor microenvironment, leading to tumor regression. Post-irradiation, the CD8α+ T cell to Treg ratio increased for 14 days, causing remote tumor regression in metastatic lesions, known as the abscopal effect. Combining BR101801 with irradiation enhances the immune-stimulatory tumor microenvironment, transforming immunologically cold tumors into hot ones, according to transcriptome analysis. Additionally, we examined CD8 T cell recruiting cells and methods. Previous studies on Batf3, which is involved in IFN-related genes and cross-presentation in cancer, were confirmed. We checked if IFNAR1 antibody administration negated the combined treatment's anticancer activity, and the result showed that only the monotherapy's effect was seen. The previously established CD8 T cell infiltration did not occur, and PMN-MDSC's immunosuppressive impact was eliminated.

Conclusions

Preclinical data indicates that PI3Kδ/γ suppression and irradiation can enhance systemic antitumor immunity against solid tumors, suggesting its potential as an immune-regulatory radiosensitizer.

Legal entity responsible for the study

Boryong Co.

Funding

Korea Institute of Radiological and Medical Sciences (KIRAMS), funded by the Ministry of Science and ICT (MSIT), The Republic of Korea (No. 50531-2021), and the National Research Foundation of Korea.

Disclosure

All authors have declared no conflicts of interest.