TSC2 S1365A mutation potently regulates CD8+ T cell function and differentiation and improves adoptive cellular cancer therapy.

Abstract

MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in the tuberous sclerosis complex tightly regulates mTORC1 activation. CD8+ T cells lacking TSC2 have constitutively enhanced mTORC1 activity and generate robust effector T cells; however, sustained mTORC1 activation prevents generation of long-lived memory CD8+ T cells. Here we show that manipulating TSC2 at Ser1365 potently regulated activated but not basal mTORC1 signaling in CD8+ T cells. Unlike nonstimulated TSC2-KO cells, CD8+ T cells expressing a phosphosilencing mutant TSC2-S1365A (TSC2-SA) retained normal basal mTORC1 activity. PKC and T cell receptor (TCR) stimulation induced TSC2 S1365 phosphorylation, and preventing this with the SA mutation markedly increased mTORC1 activation and T cell effector function. Consequently, SA CD8+ T cells displayed greater effector responses while retaining their capacity to become long-lived memory T cells. SA CD8+ T cells also displayed enhanced effector function under hypoxic and acidic conditions. In murine and human solid-tumor models, SA CD8+ T cells used as adoptive cell therapy displayed greater antitumor immunity than WT CD8+ T cells. These findings reveal an upstream mechanism to regulate mTORC1 activity in T cells. The TSC2-SA mutation enhanced both T cell effector function and long-term persistence/memory formation, supporting an approach to engineer better CAR-T cells for treating cancer.

• Authors: Chirag H Patel, Yi Dong, Navid Koleini, Xiaoxu Wang, Brittany L Dunkerly-Eyring, Jiayu Wen, Mark J Ranek, Laura M Bartle, Daniel B Henderson, Jason Sagert, David A Kass, Jonathan D Powell
• Journal: JCI insight (JCI Insight) Vol. 8 Issue 21 (Nov 08 2023) ISSN: 2379-3708 [Electronic] United States
• PMID: 37788104 (Publication Type: Journal Article)

Chemical References

• Mechanistic Target of Rapamycin Complex 1

Topics

• Mice
• Humans
• Animals
• Tuberous Sclerosis
• Mechanistic Target of Rapamycin Complex 1
• CD8-Positive T-Lymphocytes
• Mutation
• Cell Differentiation
• Tumor Microenvironment