Naive CD4+ T Cells Carrying a TLR2 Agonist Overcome TGF-β-Mediated Tumor Immune Evasion

Mohsen Ibrahim, Davide Scozzi, Kelsey A. Toth, Donatella Ponti, Daniel Kreisel, Cecilia Menna, Elena De Falco, Antonio D'Andrilli, Erino A. Rendina, Antonella Calogero, Alexander S. Krupnick, Andrew E. Gelman

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Abstract

TLR agonists are effective at treating superficial cancerous lesions, but their use internally for other types of tumors remains challenging because of toxicity. In this article, we report that murine and human naive CD4+ T cells that sequester Pam3Cys4 (CD4+ TPam3) become primed for Th1 differentiation. CD4+ TPam3 cells encoding the OVA-specific TCR OT2, when transferred into mice bearing established TGF-β-OVA-expressing thymomas, produce high amounts of IFN-γ and sensitize tumors to PD-1/ programmed cell death ligand 1 blockade-induced rejection. In contrast, naive OT2 cells without Pam3Cys4 cargo are prone to TGF-β-dependent inducible regulatory Foxp3+ CD4+ T cell conversion and accelerate tumor growth that is largely unaffected by PD-1/ programmed cell death ligand 1 blockade. Ex vivo analysis reveals that CD4+ TPam3 cells are resistant to TGF-β-mediated gene expression through Akt activation controlled by inputs from the TCR and a TLR2-MyD88-dependent PI3K signaling pathway. These data show that CD4+ TPam3 cells are capable of Th1 differentiation in the presence of TGF-β, suggesting a novel approach to adoptive cell therapy.

Original languageEnglish
Pages (from-to)847-856
Number of pages10
JournalJournal of Immunology
Volume200
Issue number2
DOIs
StatePublished - Jan 15 2018

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    Ibrahim, M., Scozzi, D., Toth, K. A., Ponti, D., Kreisel, D., Menna, C., De Falco, E., D'Andrilli, A., Rendina, E. A., Calogero, A., Krupnick, A. S., & Gelman, A. E. (2018). Naive CD4+ T Cells Carrying a TLR2 Agonist Overcome TGF-β-Mediated Tumor Immune Evasion. Journal of Immunology, 200(2), 847-856. https://doi.org/10.4049/jimmunol.1700396