Is tissue hypoxia the principal mechanism for immune evasion and malignant progression in hepatocellular carcinoma?

Cramer, Thorsten; Vaupel, Peter

doi:10.1016/j.jhep.2021.03.024

Cited by 3 publications

(1 citation statement)

References 6 publications

(5 reference statements)

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“…Hypoxia is a unique microenvironmental feature of HCC. It promotes aggressive phenotypes that increase resistance to apoptosis and favor HCC metastasis [3][4][5][6][7][8]. Hypoxia-induced HCC malignancies contribute to poor clinical prognosis.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma

Wang,

Qi,

Chen

et al. 2024

Int. J. Biol. Sci.

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Background: Hypoxia induces hepatocellular carcinoma (HCC) malignancies; yet it also offers treatment opportunities, exemplified by developing hypoxia-activated prodrugs (HAPs). Although HAP TH-302 combined with therapeutic antibody (Ab) has synergistic effects, the clinical benefits are limited by the on-target off-tumor toxicity of Ab. Here, we sought to develop a hypoxia-activated anti-M2 splice isoform of pyruvate kinase (PKM2) Ab combined with TH-302 for potentiated targeting therapy. Methods: Codon-optimized and hypoxia-activation strategies were used to develop H103 Ab-azo-PEG5k (HAP103) Ab. Hypoxia-activated HAP103 Ab was characterized, and hypoxia-dependent antitumor and immune activities were evaluated. Selective imaging and targeting therapy with HAP103 Ab were assessed in HCC-xenografted mouse models. Targeting selectivity, systemic toxicity, and synergistic therapeutic efficacy of HAP103 Ab with TH-302 were evaluated. Results: Human full-length H103 Ab was produced in a large-scale bioreactor. Azobenzene (azo)-linked PEG5k conjugation endowed HAP103 Ab with hypoxia-activated targeting features. Conditional HAP103 Ab effectively inhibited HCC cell growth, enhanced apoptosis, and induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) functions. Analysis of HCC-xenografted mouse models showed that HAP103 Ab selectively targeted hypoxic HCC tissues and induced potent tumor-inhibitory activity either alone or in combination with TH-302. Besides the synergistic effects, HAP103 Ab had negligible side effects when compared to parent H103 Ab. Conclusion: The hypoxia-activated anti-PKM2 Ab safely confers a strong inhibitory effect on HCC with improved selectivity. This provides a promising strategy to overcome the on-target off-tumor toxicity of Ab therapeutics; and highlights an advanced approach to precisely kill HCC in combination with HAP TH-302.

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Section: Introductionmentioning

confidence: 99%

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma

Wang,

Qi,

Chen

et al. 2024

Int. J. Biol. Sci.

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S100A16 is a potential target for reshaping the tumor microenvironment in the hypoxic context of liver cancer

Yang,

Zhao,

Zhou

et al. 2024

International Immunopharmacology

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Hypoxia is a key regulator in liver cancer progression

Craig

Heinrich

2021

Journal of Hepatology

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We appreciate the interest by Cramer and Vaupel in our review article on understanding tumor cell heterogeneity and its implication for immunotherapy in liver cancer by single cell analysis. 1 Cramer and Vaupel 2 questioned a statement in the article, "tumor diversity is triggered by hypoxia", which refers to our recent study on using single cell technologies to define tumor cell landscape and its biology, 3 and raised concerns about determining hypoxic status in tumours with HIF target genes since HIF can be activated by hypoxia-independent manners. We agree in general that hypoxia-mediated signaling is complex, involving the activation of HIF-1 and HIF-2 and many other players, where HIF-1 is just one of the well-characterized players in response to hypoxia. We also agree that a bioinformatics- ReferencesAuthor names in bold designate shared co-first authorship[1] Heinrich S, Craig AJ, Ma L, Heinrich B, Greten TF, Wang XW. Understanding tumour cell heterogeneity and its implication for immunotherapy in liver cancer using single-cell analysis.

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Is tissue hypoxia the principal mechanism for immune evasion and malignant progression in hepatocellular carcinoma?

Cited by 3 publications

References 6 publications

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma

S100A16 is a potential target for reshaping the tumor microenvironment in the hypoxic context of liver cancer

Hypoxia is a key regulator in liver cancer progression

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