Mechanisms of Durable Antitumor Immunity Mediated by PI3K-targeted T cells

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Project Summary The metabolic properties of T cells can influence their ability to mount effective responses against solid tumors. This limitation is particularly relevant to optimal adoptive cell therapy approaches, whereby tumor-antigen targeted T cells are administered to patients to eradicate tumors. Our team has made great progress towards overcoming this issue via our discovery that selective blockade of the PI3K p110δ isoform with CAL-101 (Idealisib®) in vitro can rewire the metabolism of T cells and render them potent upon in vivo administration to tumor bearing mice. Importantly, the durability of these T cells is associated with their enhanced mitochondrial bioenergetics and persistence, and an extraordinary capacity to mount rapid recall responses against tumor re- challenge. While mice are cured from this therapy, they often develop autoimmune vitiligo. Our newest data reveal that while PI3Kδ-inhibited T cells have stemness properties in vitro, they become tissue-resident and effector memory cells in lymphoid tissues. These provocative results imply that they may cooperate to sustain host-wide protection against metastasis by virtue of their memory phenotype and elicit vitiligo in the animal. We conducted RNAseq on these potent PI3Kδ-inhibited T cells and identified a novel oligoribonuclease, called REXO2. Our preliminary data indicates that genetic ablation of REXO2 abrogates their ability to fight tumors, but overexpressing REXO2 supports mitochondrial biogenesis, antitumor metabolism and endows T cells with efficacy as an adoptive cell therapy. These innovative data are the first to define a role for REXO2 as an actionable factor to enhance ACT. This proposal will uncover mechanisms supporting T cell metabolism and immunity in the context of REXO2 and PI3K signaling and facilitate future translational efforts for ACT with REXO2-manipulated human T cells. We hypothesize REXO2 supports metabolism of antitumor T cells and that REXO2 can be leveraged in T cells to improve the efficacy of ACT. The role of REXO2 in T cells and its therapeutic potential will be investigated in three complementary Specific Aims: AIM 1 will identify mechanisms by which PI3Kδ targeting supports antitumor T cell activity, by studying how REXO2—induced via PI3Kδ- blockade—bolsters bioenergetics to instill immunity in mice. AIM 2 will define how resident and lymphoid memory donor T cells protect mice from metastasis. Studies will also test how REXO2, sustained preferentially in skin- resident donor T cells, impacts immunity to self-versus tumor tissues. We will use human TIL and CAR T cell products generated in cancer patients and clinically-relevant xenogeneic human tumor mouse models in AIM 3, inspired by our desire to delve into studies with immediate translational significance. Namely, this work provides foundational data to generate optimized, redirected human T cells with heighted REXO2. This approach is attractive to augment immunometabolism in poorly functional T cells and empower them to mediate durable memory responses to solid tumors. Overall, the proposed research is significant, as it is expected to reveal that manipulation of REXO2 can safely protect against tumor recurrence with reduced side effects to patients.