Effect of low-dose rapamycin on the therapeutic response to radio-immunotherapy in hepatocellular carcinoma.

Abstract

e14611 Background: Numerous clinical trials have demonstrated the efficacy of combined radiotherapy and PD-1 antibody treatment in hepatocellular carcinoma (HCC). However, a significant proportion of HCC patients still exhibit suboptimal responses to this combination therapy. Recent evidence underscores the pivotal role of Tpex (T cell Exhaustion Progenitors) in mediating the response to PD-1 blockade. Therefore, maintaining sufficient Tpex represents a promising strategy for enhancing the efficacy of current radio-immunotherapy. Methods: Initially, single-cell RNA sequencing (scRNA-seq) and flow cytometry were performed on tumor-infiltrating T cells from mouse HCC tissues 5 days post-radiotherapy. Subsequently, the mechanisms underlying STING signaling and mTORC1 activation in Tpex were investigated using wild-type and STING knockout (KO) mice. Next, the correlation between mTORC1 and stem cell-like molecular markers (TCF-1, TOX, CD62L, PD-1, TIM-3, LAG-3) was examined in vitro. Finally, the systemic antitumor effects of combined radiotherapy and low-dose rapamycin treatment were evaluated in multiple HCC mouse models. Results: The infiltration level of Tpex in HCC tissues significantly decreased following repeated local radiotherapy, which relies on potent STING activation subsequent to radiotherapy. Mechanistic studies revealed that STING interacts with several components of the mTORC1 complex and plays an important role in the formation of the mTORC1 complex in Tpex under radiotherapy. Administration of low-dose rapamycin maintains the stem cell-like phenotype by restricting mTORC1-mediated metabolic switch. Lastly, combined radiotherapy with low-dose rapamycin sensitized the therapeutic effect of PD-1 antibody in multiple non-immunogenic HCC mouse models. Conclusions: Our studies demonstrate that low-dose rapamycin administration following radiotherapy effectively maintains the metabolic quiescence of Tpex, thereby supporting the response to PD-1 blockade. These findings offer a potential strategy for further sensitization of radio-immunotherapy in HCC.