Abstract
Multiple modes of immunosuppression restrain immune function within tumors. We previously reported that phosphoinositide 3-kinase δ (PI3Kδ) inactivation in mice confers resistance to a range of tumor models by disrupting immunosuppression mediated by regulatory T cells (Tregs). The PI3Kδ inhibitor idelalisib has proven highly effective in the clinical treatment of chronic lymphocytic leukemia and the potential to extend the use of PI3Kδ inhibitors to nonhematological cancers is being evaluated. In this work, we demonstrate that the antitumor effect of PI3Kδ inactivation is primarily mediated through the disruption of Treg function, and correlates with tumor dependence on Treg immunosuppression. Compared with Treg-specific PI3Kδ deletion, systemic PI3Kδ inactivation is less effective at conferring resistance to tumors. We show that PI3Kδ deficiency impairs the maturation and reduces the capacity of CD8+ cytotoxic T lymphocytes (CTLs) to kill tumor cells in vitro, and to respond to tumor antigen-specific immunization in vivo. PI3Kδ inactivation antagonized the antitumor effects of tumor vaccines and checkpoint blockade therapies intended to boost the CD8+ T cell response. These findings provide insights into mechanisms by which PI3Kδ inhibition promotes antitumor immunity and demonstrate that the mechanism is distinct from that mediated by immune checkpoint blockade.
Highlights
Modulation of the immune response as a therapeutic strategy for cancer has proven to be a successful approach in some cancers
Studies using checkpoint blockade antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) or the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis have focused on the enhancement of CD8+ T cell activity [1,2,3]
The phosphoinositide 3-kinase δ (PI3Kδ) pathway is engaged by the T cell receptor (TCR), the interleukin 2 (IL-2) receptor, and costimulatory receptors, and its inhibition could influence the effector immune response required for tumor clearance [6, 7]
Summary
Modulation of the immune response as a therapeutic strategy for cancer has proven to be a successful approach in some cancers. The challenge, is to define conditions that optimize the beneficial effect of PI3Kδ inhibition on Tregs while minimizing adverse effects on effector T cell (Teff) populations during antitumor immune responses. The PI3Kδ inhibitor idelalisib has recently been approved for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma [8, 9]. In these B cell cancers, PI3Kδ plays an important cell-intrinsic role, but may affect cells in the tumor microenvironment [10, 11]. To fully realize the potential of PI3Kδ inhibitors and for the optimal design of patient stratification and combinatorial therapies, it is imperative to further elucidate the impact of PI3Kδ inhibition on tumor immunity
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