Abstract A222: Exploiting mTORC1-independent protein synthesis in Tregs to boost antitumor immune response

Abstract

Regulatory T-cells (Tregs) maintain immune system homeostasis in the organism. In the tumor micro-environment, however, Tregs can hinder antitumor immune response. Treg maturation in peripheral sites (pTregs) requires inhibition of protein kinase mTORC1, which paradoxically blocks mRNA translation. mTORC1 phosphorylates (inactivates) 4E-BP1, a negative regulator of the translation initiation factor eIF4E. When mTORC1 is active, 4E-BP1 is hyperphosphorylated and releases eIF4E, which can then bind the mRNA cap structure and promote eIF4F complex assembly and ribosome recruitment. Inhibition of mTORC1 results in hypo-phosphorylation (activation) of 4E-BP1, which then binds and sequesters eIF4E, preventing its interaction with the cap and ribosome association to the mRNA. Using human CD4+ T-cells differentiated in vitro, we show that mTORC1 inhibition strongly impairs protein synthesis, yet with exposure to TGFbeta, is essential to mediate iTreg differentiation and immune suppression activity. We found that TGFbeta reprograms the T-cell transcriptome, while mTORC1 inhibition reprograms the translatome (genome-wide translation signature), mediating Treg differentiation. Genome-wide transcription and translation profiling identified TGFbeta-upregulated mRNAs resistant to mTORC1 inhibition, in part due to their 5’-untranslated regions, that induces Treg differentiation and immune suppression activity. These include canonical pTreg fate-determining mRNAs FOXP3, CTLA-4, CD101 and CD103, among others. Inhibition of mTORC1 alone or TGFbeta alone induces iTregs with poor immune suppression activity. Treg differentiation is therefore mediated by an mTORC1-independent privileged mRNA translation mechanism that converts activated CD4+ T-cells to Tregs. These findings are quite relevant in the tumor microenvironment, where mTORC1-inhibiting conditions such as hypoxia and deprivation of nutrients and energy are present. Investigation of molecular targets acting in this mTORC1/eIF4E-independent translation of Treg mRNAs is ongoing. These targets could be drugged to selectively inhibit Treg differentiation in the tumor microenvironment, thus allowing effector cells to mount the response against cancer cells. Citation Format: Viviana Volta, Amanda Ernlund, Columba De la Parra, Abilash Gadi, Amanda Valeta-Magara, Robert J. Schneider. Exploiting mTORC1-independent protein synthesis in Tregs to boost antitumor immune response [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A222.