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.

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.

• Authors: Siqi Li, Kun Li, Kang Wang, Haoyuan Yu, Xiangyang Wang, Mengchen Shi, Zhixing Liang, Zhou Yang, Yongwei Hu, Yang Li, Wei Liu, Hua Li, Shuqun Cheng, Linsen Ye, Yang Yang
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 7709 (Nov 24 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 38001101 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• B7-H1 Antigen
• Bevacizumab
• VEGFA protein, human
• Vascular Endothelial Growth Factor A

Topics

• Humans
• Carcinoma, Hepatocellular (radiotherapy, drug therapy)
• CD8-Positive T-Lymphocytes (pathology)
• B7-H1 Antigen
• Liver Neoplasms (therapy, pathology)
• Bevacizumab (pharmacology, therapeutic use)
• Cell Line, Tumor
• Vascular Endothelial Growth Factor A