593 PI3Kγδ inhibitor combined with radiation enhances the antitumor immune effect of PD-1 blockade in syngenic murine breast cancer model and humanized patient-derived xenograft model
Abstract
Breast cancer is viewed as immunologically cold, imposing an immune-suppressive tumor microenvironment and responding poorly to lone immune checkpoint blockade. As an adjunct to ICB, radiation therapy holds promise in terms of in situ tumor vaccination effect, although it is known to promote immune suppression, increasing regulatory T cells, myeloid-derived suppressor cell, and M2 tumor-associated macrophages. It was our contention that combined use of RT and a PI3Kγδ inhibitor to combat immune suppression might enhance the efficacy of ICB.Murine breast cancer cells (4T1) were grown in both immune-competent and -deficient BALB/c mice, and tumors were irradiated by 3 fractions of 24 Gy. A PD-1 blockade and a PI3Kγδ inhibitor were then administered every other day for 2 weeks. Tumors from humanized patient-derived breast cancer xenograft model was sequenced to identify immune-related pathways and to 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.In the immune-competent syngenic 4T1 murine tumor model, PD-1 blockade alone led to tumor hyperprogression, whereas a three-pronged strategy of PI3Kγδ inhibitor, RT, and PD-1 blockade significantly delayed primary tumor growth, boosted abscopal effect, and improved animal survival by comparison. The immune-deficient syngenic 4T1 murine tumor model failed to show this synergism in…
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Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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