Carnevalli and Sinclair et al. explored the effect of a dual PI3Kα/δ inhibitor (typically used to directly target tumor cells) on immune cells in the TME and found that it showed strong antitumor efficacy on an intermittent dosing schedule in various murine tumor models. PI3Kα/δ inhibition induced dynamic suppression of Tregs, promoted an inflammatory signature, and increased infiltration by antitumor immune cells, including CD8+ T cells. Independent from the effect of Treg suppression, PI3Kα/δ inhibition directly increased the survival and activation of CD8+ T cells, likely via induction of IL-2 autocrine signaling in weakly activated T cells.

PI3K inhibitors with differential selectivity to distinct PI3K isoforms have been tested extensively in clinical trials, largely to target tumor epithelial cells. PI3K signaling also regulates the immune system and inhibition of PI3Kdelta modulate the tumor immune microenvironment of pre-clinical mouse tumor models by relieving T-regs-mediated immunosuppression. PI3K inhibitors as a class and PI3Kdelta specifically are associated with immune-related side effects. However, the impact of mixed PI3K inhibitors in tumor immunology is under-explored. Here we examine the differential effects of AZD8835, a dual PI3Kalpha/delta inhibitor, specifically on the tumor immune microenvironment using syngeneic models. Continuous suppression of PI3Kalpha/delta was not required for anti-tumor activity, as tumor growth inhibition was potentiated by an intermittent dosing/schedule in vivo. Moreover, PI3Kalpha/delta inhibition delivered strong single agent anti-tumor activity, which was associated with dynamic suppression of T-regs, improved CD8(+) T-cell activation and memory in mouse syngeneic tumor models. Strikingly, AZD8835 promoted robust CD8(+) T-cell activation dissociated from its effect on T-regs. This was associated with enhancing effector cell viability/function. Together these data reveal novel mechanisms by which PI3Kalpha/delta inhibitors interact with the immune system and validate the clinical compound AZD8835 as a novel immunoncology drug, independent of effects on tumor cells. These data support further clinical investigation of PI3K pathway inhibitors as immuno-oncology agents.

Author Info: (1) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. Larissa.Carnevalli@astrazeneca.com. (2) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave

Author Info: (1) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. Larissa.Carnevalli@astrazeneca.com. (2) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. (3) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. (4) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. (5) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. Present Address: University of Birmingham, B15 2TT, Birmingham, UK. (6) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. (7) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Alderley Park, Alderley Edge, Macclesfield, SK10 4TG, UK. Present Address: Alderley Park Limited, Preclinical Services, Alderley Park, Macclesfield, SK10 4TG, UK. (8) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. (9) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. (10) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. (11) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. (12) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. (13) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. (14) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Alderley Park, Alderley Edge, Macclesfield, SK10 4TG, UK. Present Address: 2theNth, Adelphi Group, Bollington, SK10 5JB, UK. (15) Bioscience, Oncology, IMED Biotech Unit AstraZeneca, Francis Crick Ave, Cambridge, CB2 0SL, UK. Simon.T.Barry@astrazeneca.com.

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