PI3K gamma delta inhibitor plus radiation enhances the antitumour immune effect of PD-1 blockade in syngenic murine breast cancer and humanised patient-derived xenograft model

Abstract

Introduction: We hypothesised that the combined use of radiation therapy and a phosphoinositide 3-kinase gamma delta inhibitor to reduce immune suppression would enhance the efficacy of an immune checkpoint inhibitor. Methods: Murine breast cancer cells (4T1) were grown in both immune-competent and -deficient BALB/c mice, and tumours were irradiated by 3 fractions of 24 Gy. A PD-1 blockade and a phosphoinositide 3-kinase (PI3K)gamma delta inhibitor were then administered every other day for 2 weeks. The same experiments were performed in humanised patient-derived breast cancer xenograft model and its tumour was sequenced to identify immune-related pathways and profile infiltrated immune cells. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas pan-cancer cohort, and the deconvolution algorithm was used to profile immune cell repertoire. Results: Using a PI3K gamma delta inhibitor, radiation therapy (RT) and PD-1 blockade significantly delayed primary tumour growth, boosted the abscopal effect and improved animal survival. RT significantly increased CD8+cytotoxic T-cell fractions, immune-suppressive regulatory T cells (T-regs), myeloid-derived suppressor cells and M2 tumour-associated macrophages (TAMs). However, the PI3K gamma delta inhibitor significantly lowered the proportions of T-regs, myeloid-derived suppressor cells and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumour CD8+ T-cell populations after triple combination therapy. In a humanised patient-derived breast cancer xenograft model, triple combination therapy significantly delayed tumour growth and decreased immune-suppressive pathways. In The Cancer Genome Atlas cohort, high T-reg/CD8+ T cell and M2/M1 TAM ratios were associated with poor overall patient survival. Conclusion: These findings indicate PI3K gamma and PI3K delta are clinically relevant targets in an immunosuppressive TME, and combining PI3K gamma delta inhibitor, RT and PD-1 blockade may overcome the therapeutic resistance of immunologically cold tumours. Synopsis: Combining PI3K gamma delta inhibitor, RT, and PD-1 blockade may be a viable clinical approach, helping to overcome the therapeutic resistance of immunologically cold tumours such as breast cancer. (C) 2021 Elsevier Ltd. All rights reserved.