RT Journal Article SR Electronic T1 Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e002279 DO 10.1136/jitc-2020-002279 VO 9 IS 8 A1 Sho Isoyama A1 Shigeyuki Mori A1 Daisuke Sugiyama A1 Yasuhiro Kojima A1 Yasuko Tada A1 Kohei Shitara A1 Kunihiko Hinohara A1 Shingo Dan A1 Hiroyoshi Nishikawa YR 2021 UL http://jitc.bmj.com/content/9/8/e002279.abstract AB Background Immune checkpoint blockade (ICB) induces durable clinical responses in patients with various types of cancer. However, its limited clinical efficacy requires the development of better approaches. In addition to immune checkpoint molecules, tumor-infiltrating immunosuppressive cells including regulatory T cells (Tregs) play crucial roles in the immune suppressive tumor microenvironment. While phosphatidylinositol 3-kinase (PI3K) inhibition as a Treg-targeted treatment has been implicated in animal models, its effects on human Tregs and on the potential impairment of effector T cells are required to be clarified for successful cancer immunotherapy.Methods The impact of a selective-PI3K inhibitor ZSTK474 with or without anti-programmed cell death 1 (PD-1) monoclonal antibody on Tregs and CD8+ T cells were examined with in vivo animal models and in vitro experiments with antigen specific and non-specific fashions using peripheral blood from healthy individuals and cancer patients. Phenotypes and functions of Tregs and effector T cells were examined with comprehensive gene and protein expression assays.Results Improved antitumor effects by the PI3K inhibitor in combination with ICB, particularly PD-1 blockade, were observed in mice and humans. Although administration of the PI3K inhibitor at higher doses impaired activation of CD8+ T cells as well as Tregs, the optimization (doses and timing) of this combination treatment selectively decreased intratumoral Tregs, resulting in increased tumor antigen-specific CD8+ T cells in the treated mice. Moreover, on the administration of the PI3K inhibitor with the optimal dose for selectively deleting Tregs, PI3K signaling was inhibited not only in Tregs but also in activated CD8+ T cells, leading to the enhanced generation of tumor antigen-specific memory CD8+ T cells which contributed to durable antitumor immunity. These opposing outcomes between Tregs and CD8+ T cells were attributed to the high degree of dependence on T cell signaling in the former but not in the latter.Conclusions PI3K inhibitor in the combination with ICB with the optimized protocol fine-tuned T cell activation signaling for antitumor immunity via decreasing Tregs and optimizing memory CD8+ T cell responses, illustrating a promising combination therapy.Data are available on reasonable request. The datasets generated and analyzed during the current study are not publicly available due to their relevance only for the study presented here but are available from the corresponding author on reasonable request.