T 细胞干性程度以依赖 Lef-1 和 Tcf-1 的方式差异性影响过继性肿瘤免疫治疗的效力

Generating stem memory T cells (T SCM ) is a key goal for improving cancer immunotherapy. Yet, the optimal way to modulate signaling pathways that enrich T SCM properties remains elusive.

Here, we discovered that the degree to which the PI3K pathway is blocked pharmaceutically can generate T cells with differential levels of stemness properties. This observation was based on the progressive enrichment of transcriptional factors of stemness (Tcf-1 and Lef-1). Additional investigation revealed that T cells with high stemness features had enhanced metabolic plasticity, marked by heightened mitochondrial function and glucose uptake.

Conversely, T cells with low or medium features of stemness expressed more inhibitory checkpoint receptors (Tim-3, CD39) and were vulnerable to antigen-induced cell death. Only TCR-antigen specific T cells with high stemness persisted following adoptive transfer in vivo and mounted protective immunity to melanoma tumors. Likewise, the strongest level of PI3K blockade in vitro generated human tumor infiltrating lymphocytes (TILs) and CAR T cells with heightened stemness properties, in turn bolstering their capacity to regress human mesothelioma tumors.

We find that the level of stemness T cells possess in vitro differentially impacts their potency upon transfer in three tumor models.

Mechanistically, both Lef-1 and Tcf-1 sustain anti-tumor protection by high T SCM , as deletion of either one compromised cellular therapy. Collectively, these findings highlight the therapeutic potential of carefully modulating PI3K signaling in T cells to confer high stemness and mediate protective responses to solid tumors.