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

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⁺ T^Pam3) become primed for T_h1 differentiation. CD4⁺ T^Pam3 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⁺ T^Pam3 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⁺ T^Pam3 cells are capable of T_h1 differentiation in the presence of TGF-β, suggesting a novel approach to adoptive cell therapy.