Targeting PI3K Isoforms to Improve Effectiveness of T Cells Mediated Immunotherapy

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The hyperactivation of the PI3K pathway is associated with immune checkpoint blockade (ICB) resistance in cancer patients, highlighting the potential of combining PI3K inhibitor with ICB. Different PI3K isoforms are suggested to play a role in tumors and T cells, offering an opportunity to precisely target tumors without affecting T cells. Previous research demonstrated the synergy between a PI3KB inhibitor with ICB in PTEN loss melanoma, but the patient population is limited. To expand the therapeutic window in PTEN-present tumors, additional strategies are needed. Literature research identified a knowledge gap regarding the roles of PI3K isoforms in tumor cells and T cells, which hindered the exploration of PI3K inhibitors and ICB combinations. To address this gap, we conducted a study using genetic knockdown and pharmacological intervention to characterize the functional roles of PI3K isoforms in tumor and T cells. Our findings revealed that inhibiting either PI3Ka or PI3KB reduced the PI3K pathway activity in tumor cells while minimally impacting T cells. Moreover, inhibiting PI3Ky or PI3Ko suppressed. PI3K activation, cytokine production, and cytotoxicity of T cells, suggesting that targeting PI3K⍺ or PI3KB isoforms can achieve tumor-specific PI3K inhibition with limited effects on T cell function. Our in vivo studies demonstrated that PI3Ka inhibitor synergizes with ICB to delay tumor growth, improve T cell infiltration, and reduce MDSCs in PTEN-present tumors. However, we observed limited synergistic effects of PI3KB inhibitor and ICB in PTEN-present tumors. Multiomics profiling revealed the upregulation of TNF-a signaling in PTEN-present tumors and the upregulation of genes associated with cell cycle, apoptosis, and immune response in PTEN-absent tumors after PI3Ka inhibition. In conclusion, our results provide a strong rationale for the clinical development of PI3Ka inhibitor-based combination immunotherapy in patients with solid tumors.

PI3K, Immunotherapy, CD8+, T cells, ICB