Thymosin alpha-1 restores chemotherapy-induced antitumor immunity by chaperoning a microRNA ligand of TLR7 in dendritic cells
Chemotherapy induces tumor apoptosis and the release of apoptotic bodies (ABs) that are poorly immunogenic or immunosuppressive, creating a major barrier to the success of co-administered or second-line immunotherapies. Here, we find that patients with multiple types of cancer and mice bearing established tumors have reduced circulating levels of thymosin alpha-1 (Ta-1), a key endogenous peptide hormone with obscure immunomodulatory mechanisms despite many experimental or empirical uses, after chemotherapy. Ta-1 binds to tumor ABs and interacts with AB-borne endogenous microRNAs, including miR146a-5p, following ABs phagocytosis into the endolysosomal compartment of dendritic cells (DCs). This interaction protects miR146a-5p from lysosomal RNase A-mediated degradation, allowing miR146a-5p-mediated activation of Toll-like receptor 7 (TLR7) that licenses DC maturation and migration to tumor-draining lymph nodes and the presentation of tumor antigens to activate tumor-specific CD8+ T cells. Therapeutic Ta-1 supplementation produces strong synergy with chemotherapy to control established tumors in mice with high miR146a-5p expression in a TLR7-dependent manner. These findings establish Ta-1 as a previously overlooked but pivotal endogenous microRNA chaperone that unlocks a critical limiting step of DC licensing, empowering robust antitumor immunity after chemotherapy.