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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.

SUBMITTER: Li S

PROVIDER: S-EPMC10673920 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8<sup>+</sup> exhausted-like T cells.

Li Siqi S Li Kun K Wang Kang K Yu Haoyuan H Wang Xiangyang X Shi Mengchen M Liang Zhixing Z Yang Zhou Z Hu Yongwei Y Li Yang Y Liu Wei W Li Hua H Cheng Shuqun S Ye Linsen L Yang Yang Y

Nature communications 20231124 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<sup>+</sup> T cells in various preclinica ...[more]

PMID: 38001101

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Project description:BackgroundLiver metastasis is highly aggressive and immune tolerant, and lacks effective treatment strategies. This study aimed to develop a neoantigen hydrogel vaccine (NPT-gels) with high clinical feasibility and further investigate its efficacy and antitumor molecular mechanisms in combination with immune checkpoint inhibitors (ICIs) for the treatment of liver metastases.MethodsThe effects of liver metastasis on survival and intratumor T-cell subpopulation infiltration in patients with advanced tumors were investigated using the Surveillance, Epidemiology, and End Results Program (SEER) database and immunofluorescence staining, respectively. NPT-gels were prepared using hyaluronic acid, screened neoantigen peptides, and dual clinical adjuvants [Poly(I:C) and thymosin α-1]. Then, the efficacy and corresponding antitumor molecular mechanisms of NPT-gels combined with programmed death receptor 1 and cytotoxic T-lymphocyte-associated protein 4 double blockade (PCDB) for the treatment of liver metastases were investigated using various preclinical liver metastasis models.ResultsLiver metastases are associated with poorer 5-year overall survival, characterized by low infiltration of cytotoxic CD8+ T cells and high infiltration of regulatory T cells (Tregs). NPT-gels overcame the challenges faced by conventional neoantigen peptide vaccines by sustaining a durable, high-intensity immune response with a single injection and significantly improving the infiltration of neoantigen-specific T-cell subpopulations in different mice subcutaneous tumor models. Importantly, NPT-gels further combined with PCDB could enhance neoantigen-specific T-cell infiltration and effectively unlock the immunosuppressive microenvironment of liver metastases, showing superior antitumor efficacy and inducing long-term immune memory in various preclinical liver metastasis models without obvious toxicity. Mechanistically, the combined strategy can inhibit Tregs, induce the production and infiltration of neoantigen-specific CD8+CD69+ T cells to enhance the immune response, and potentially elicit antigen-presenting effects in Naïve B_Ighd+ cells and M1-type macrophages.ConclusionsThis study demonstrated that NPT-gels combined with PCDB could exert a durable and powerful antitumor immunity by enhancing the recruitment and activation of CD8+CD69+ T cells, which supports the rationale and clinical translation of this combination strategy and provides important evidence for further improving the immunotherapy efficacy of liver metastases in the future.

Dataset Information

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.

Publications

Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8<sup>+</sup> exhausted-like T cells.

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Dataset Information

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.

Publications

Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8&lt;sup&gt;+&lt;/sup&gt; exhausted-like T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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.

Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8<sup>+</sup> exhausted-like T cells.