Reprogramming Inflammatory Tumor Microenvironment Enhances anti-PD-L1 Cancer Immunotherapy by Vascular Normalization

  • Date: 2021-08-16
  • Update: 2021-08-17
  • Source: 國家衛生研究院
  • Views: 314


Reprogramming Inflammatory Tumor Microenvironment Enhances anti-PD-L1 Cancer Immunotherapy by Vascular Normalization

─NHRI has revealed a new mechanism of how mitochondria regulate cancer immunoescape through mtDNA in an inflammatory TME and developed a novel VEGF fusion protein to reduce immunosuppression and enhance cancer immunotherapy ─

August 16, 2021

Immunotherapy is an emerging approach that may have great potential against cancer. Immune checkpoint inhibitors (e.g., anti-PD-1), however, have response rates of only 10–30% in solid tumors because of the immunosuppressive tumor microenvironment (TME). The efficacy of cancer immunotherapy is influenced by the status of the TME, which regulates inflammation and immunoescape. Scientists with Taiwan’s National Health Research Institutes have discovered that mitochondria regulate ROS-dependent cancer immunoescape through mtDNA metabolism in the TME. Mitochondrial Lon-induced oxidative stress persuades mtDNA damage and promotes mtDNA release into the cytosol. mtDNA release induces IFN signaling through the STING-dependent pathway upon oxidative stress. Furthermore, the Lon-mtDNA axis induces the expression of PD-L1. Lon overexpression-induced EVs further induce the production of IFN, IL-6, and VEGF-A from macrophages and further induce angiogenesis and inhibit T cell function. The results of this study were published in the Journal for ImmunoTherapy of Cancer, the official journal of the Society for Immunotherapy of Cancer. The society is based in the United States but has members in 42 countries throughout the world.

The immunosuppressive affliction can be solved by vascular normalization and TME reprogramming. Using in vitro and in vivo study, the researchers further developed the VEGF121–VEGF165 fusion protein (VFD) and determined that it arrests excess angiogenesis and tumor growth. Since the TME plays a major role in cancer immunotherapy, they tried to use vascular normalization as a strategy by VEGF121–VEGF165 to increase immune cell infiltration. The results showed that treatment with VFD increases immune cell infiltration — including cytotoxic T, NK, and M1-macrophage cells — which reprograms the immunosuppressive TME. Importantly, VFD has a synergistic effect in vivo with anti-PD-L1 on the combination immunotherapy.

The key concepts and technologies relevant to this invention were recognized with a National Innovation Award, and are protected by important international patents, including ones in the United States (no. 10,851,142 B2) and Japan. Preclinical evaluations — such as pharmacokinetic modelling (ADME) and toxicity, and a preclinical test on comparative oncology — are being undertaken in preparation for a clinical trial application. 

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