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

• Published in: Nature communications 2023-11, Vol.14 (1), p.7709-7709, Article 7709
• Main Authors: Li, Siqi, Li, Kun, Wang, Kang, Yu, Haoyuan, Wang, Xiangyang, Shi, Mengchen, Liang, Zhixing, Yang, Zhou, Hu, Yongwei, Li, Yang, Liu, Wei, Li, Hua, Cheng, Shuqun, Ye, Linsen, Yang, Yang
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 13/31; 13/51; 38/77; 38/91; 42; 59/57; 631/67/1504/1610/4029; 692/4028/67/1059; 692/4028/67/1059/485; 692/4028/67/580; 82/51; Anticancer properties; Antitumor activity; Bevacizumab; CD8 antigen; Combinatorial analysis; CXCL10 protein; CXCR3 protein; Effectiveness; Effector cells; Hepatocellular carcinoma; Humanities and Social Sciences; Immunotherapy; Liver cancer; Lymph nodes; Lymphocytes; Lymphocytes T; multidisciplinary; PD-L1 protein; Progenitor cells; Radiation dosage; Radiation therapy; Science; Science (multidisciplinary); Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-43462-1

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. An increasing number of preclinical and clinical studies have investigated the antitumor efficacy of combined radiotherapy and immunotherapy. Here the authors report that low-dose radiotherapy enhances the antitumor effect of dual VEGFA and PD-L1 blockade in preclinical models of hepatocellular carcinoma.