Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation

Abstract

A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression of RAS homolog enriched in brain (RHEB) increased mTORC1 signaling, promoted a switch to aerobic glycolysis, and increased expansion of effector T cells. By rapidly infiltrating tumors, RHEBtransduced T cells significantly reduced the emergence of immunoedited escape variants. In contrast, expression of proline-rich Akt substrate of 40 kDa (PRAS40) inhibited mTORC1, promoted quiescence, and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1 low T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T-cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal. Unlike pharmacologic inhibitors, the genetic approach described here allows for upregulation as well as inhibition of the mTORC1 pathway and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions. Cancer Res; 75(13); 2641-52. Ó2015 AACR.

Chimeric antigen receptor T-cell therapy for solid tumors

“…, the mammalian target of rapamycin) might augment the efficacy of adoptively transferred cells. 34 Sukumar and colleague also showed that inhibiting glycolysis promoted the formation of memory cells, and enhanced antitumor activity. 35 …”

PRAS40 signaling in tumor

“…Activated mTORC1 accelerates T-cell infiltration at the tumor site and exerts more aggressive immune pressure on the growing tumors, which is associated with the prevention of tumor escape. Overexpression of PRAS40 in T cells decreases the mTORC1 signaling, promotes the T cell quiescence and blocks the tumor infiltration of the T cells in vitro and in vivo [ 68 ].…”

Advances in chimeric antigen receptor T-cell immunotherapy (CAR-T) in glioma

“…Some studies have shown that introducing the key cell regulator-mammalian target of rapamycin (mTOR), which controls protein synthesis, is beneficial to the survival and proliferation of CAR-T cells. 30 At the same time, rat sarcoma protein homologues enriched in the brain, increased mTORC1 signal transduction, promoted the conversion to aerobic glycolysis, and increased the expansion of effector T cells.…”