Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells
Siqi Li, Kun Li, Kang Wang, Haoyuan Yu, Xiang‐Yang Wang, Mengchen Shi, Zhixing Liang, Yang Zhou, Yongwei Hu, Yang Li, Wei Liu, Hua Li, Shuqun Cheng, Linsen Ye, Yang Yang
Abstract
Abstract Atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but the number of patients who benefit from this regimen remains limited. Here, we combine dual PD-L1 and VEGFA blockade (DPVB) with low-dose radiotherapy (LDRT), which rapidly inflames tumors, rendering them vulnerable to immunotherapy. The combinatorial therapy exhibits superior antitumor efficacy mediated by CD8 + T cells in various preclinical HCC models. Treatment efficacy relies upon mobilizing exhausted-like CD8 + T cells (CD8 + Tex) with effector function and cytolytic capacity. Mechanistically, LDRT sensitizes tumors to DPVB by recruiting stem-like CD8 + Tpex, the progenitor exhausted CD8 + T cells, from draining lymph nodes (dLNs) into the tumor via the CXCL10/CXCR3 axis. Together, these results further support the rationale for combining LDRT with atezolizumab and bevacizumab, and its clinical translation.