Thymosin Alpha-1 Restores Chemotherapy-Induced Antitumor Immunity by Chaperoning miR146a-5p to Activate TLR7 in Dendritic Cells

Chemotherapy, while effective at killing cancer cells, often releases apoptotic bodies (ABs) that are poorly immunogenic or even immunosuppressive. This creates a significant hurdle for successful co-administered or subsequent immunotherapies, limiting their efficacy. A critical gap exists in strategies to 're-license' the immune system after chemotherapy to mount a robust antitumor response. Thymosin Alpha-1 (Tα-1), an endogenous immunomodulatory peptide, is being investigated for its potential to bridge this gap by enhancing dendritic cell (DC) maturation and T-cell activation, particularly via Toll-like receptor (TLR) signaling.

Researchers first observed reduced circulating Thymosin Alpha-1 (Tα-1) levels in patients with various cancers and in mice bearing established tumors after chemotherapy. They then investigated Tα-1's mechanism, finding it bound to tumor apoptotic bodies (ABs) and their associated microRNAs, specifically miR146a-5p, following phagocytosis by dendritic cells (DCs). The study used in vitro assays to demonstrate Tα-1's protective effect on miR146a-5p from RNase A degradation. Finally, therapeutic Tα-1 supplementation was administered to mice with established tumors receiving chemotherapy to assess its impact on tumor control and immune activation, focusing on TLR7 dependence.

Circulating Thymosin Alpha-1 (Tα-1) levels were consistently found to be reduced after chemotherapy in both cancer patients and tumor-bearing mice. Mechanistically, Tα-1 was shown to bind to tumor apoptotic bodies (ABs) and interact with AB-borne microRNAs, including miR146a-5p, within the endolysosomal compartment of dendritic cells (DCs). This interaction was crucial: Tα-1 protected miR146a-5p from lysosomal RNase A-mediated degradation, allowing it to activate Toll-like receptor 7 (TLR7). This TLR7 activation subsequently licensed DC maturation, facilitated their migration to tumor-draining lymph nodes, and enabled the presentation of tumor antigens to activate tumor-specific CD8+ T cells.

Therapeutic Tα-1 supplementation produced strong synergy with chemotherapy, significantly enhancing control of established tumors in mice, particularly those with high miR146a-5p expression, in a TLR7-dependent manner.