Enhanced Therapeutic Efficacy and Memory of Tumor-Specific CD8 T Cells by Ex Vivo PI3K-δ Inhibition

Abstract

Inhibition of specific Akt isoforms in CD8+ T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating anti-tumor immunity. In this study, we investigated the role of upstream PI3K isoforms in CD8+ T cell differentiation and assessed the potential use of PI3K isoform-specific inhibitors to favorably condition CD8+ T cells for adoptive cell therapy. The phenotype and proliferative ability of tumor antigen specific CD8+ T cells was assessed in the presence of PI3K-α, -β, or -δ inhibitors.Inhibition of PI3K-δ, but not PI3K-α or PI3K-β, delayed terminal differentiation of CD8+ T cells and maintained the memory phenotype, thus enhancing their proliferative ability and survival while maintaining their cytokine and granzyme B production ability. This effect was preserved in vivo after of ex vivo PI3K-δ inhibition in CD8+ T cells destined for adoptive transfer, enhancing their survival and also the anti-tumor therapeutic activity of a tumor-specific peptide vaccine.Our results outline a mechanism by which inhibitions of a single PI3K isoform can enhance the proliferative potential, function and survival of CD8+ T cells, with potential clinical implications for adoptive cell transfer and vaccine-based immunotherapies.

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

“…1-3,5-9,15-21,24,25,29-35 This could be accomplished by inhibition of the AKT pathway, as was previously shown by us and others. 15-21 In this study, we aimed to further optimize AKT-inhibited CD8 + T cells by exploring AKT-inhibitors with diverse modality of action, and further characterize these cells for their phenotype, transcriptome, metabolism and functionality. Here, we showed that both allosteric and ATP-competitive AKT-inhibitors retain T cells in an early memory state, do not hamper the expansion of MiHA-specific CD8 + T cells, and facilitate generation of polyfunctional T cells for adoptive cell therapy.…”

“…1-3,5-9,25,29,32,34 This perspective should promote further research and clinical translation of adoptive T cell therapy with interference of the PI3K/AKT/mTOR or Wnt-signalling pathway. 15-19,21,33 Here we show that AKT-inhibition can be used for the generation of a unique T SCM -like CD8 + T cell product for adoptive transfer. Though this is irrespective of the mode of action of the inhibitor, the choice of inhibitor does influence the characteristics and, thereby, possibly the clinical potency of the therapeutic product.…”

“…This uncoupling of T cell differentiation from expansion using AKT-inhibitors has been confirmed in other models, including melanoma-derived tumor-infiltrating lymphocytes and CD19 CAR T cells, as well as by modulation of up- and down-stream targets of the AKT-pathway, including mTORC2 and PI3K-δ. 16-18,20,21 …”

Reinforce the antitumor activity of CD8+ T cells via glutamine restriction

“…Complementary reports have shown that differentiation into memory cells enhances the antitumor activity of tumor‐specific CD8 + T cells without reducing their effector functions . In addition, preclinical studies of ACT have revealed that memory cells can mediate an enhanced antitumor response compared with effectors .…”

Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors

“…Intermittent dosing with PI3K inhibitors, or dosing PI3K inhibitors sequentially with immune checkpoint inhibitors, may be strategies worth considering. In fact, the inhibition of PI3Kδ during the in vitro expansion of T cells subsequently used for adoptive cell therapy enhances tumor rejection in mice, potentially by expanding a subset of CD8 + T cells with stem cell-like properties that may allow for a more persistent attack on the tumors (40)(41)(42). The challenge therefore will be to harness this potential to enhance the durability of the CD8 + T cell response while inhibiting Treg-mediated suppression.…”