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, Xiangyang Wang, Mengchen Shi, Zhixing Liang, Zhou Yang, Yongwei Hu, Yang Li, Wei Liu, Hua Li (), Shuqun Cheng (), Linsen Ye () and Yang Yang ()
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Siqi Li: The Third Affiliated Hospital of Sun Yat-sen University
Kun Li: The Third Affiliated Hospital of Sun Yat-sen University
Kang Wang: Naval Medical University
Haoyuan Yu: The Third Affiliated Hospital of Sun Yat-sen University
Xiangyang Wang: The Seventh Affiliated Hospital of Sun Yat-sen University
Mengchen Shi: Sun Yat-sen University
Zhixing Liang: The Third Affiliated Hospital of Sun Yat-sen University
Zhou Yang: The Third Affiliated Hospital of Sun Yat-sen University
Yongwei Hu: The Third Affiliated Hospital of Sun Yat-sen University
Yang Li: The Third Affiliated Hospital of Sun Yat-sen University
Wei Liu: The Third Affiliated Hospital of Sun Yat-sen University
Hua Li: The Third Affiliated Hospital of Sun Yat-sen University
Shuqun Cheng: Naval Medical University
Linsen Ye: The Third Affiliated Hospital of Sun Yat-sen University
Yang Yang: The Third Affiliated Hospital of Sun Yat-sen University

Nature Communications, 2023, vol. 14, issue 1, 1-21

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.

Date: 2023
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DOI: 10.1038/s41467-023-43462-1

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