2. Academic Validation
  3. Pharmacologic Suppression of B7-H4 Glycosylation Restores Antitumor Immunity in Immune-Cold Breast Cancers

Pharmacologic Suppression of B7-H4 Glycosylation Restores Antitumor Immunity in Immune-Cold Breast Cancers

  • Cancer Discov. 2020 Dec;10(12):1872-1893. doi: 10.1158/2159-8290.CD-20-0402.
Xinxin Song  # 1,  Zhuan Zhou  # 1,  Hongchun Li  # 2 3,  Yifan Xue 4,  Xinghua Lu 4,  Ivet Bahar 3,  Oliver Kepp 5,  Mien-Chie Hung 6,  Guido Kroemer 5 7 8 9,  Yong Wan 10
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Department of Pharmacology, the Robert H. Lurie Comprehensive Cancer Center, Chemistry of Life Process Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
  • 2 Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Beijing, China.
  • 3 Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  • 4 Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  • 5 Equipe labellisée par la Ligue contre le Cancer, Université de Paris, Sorbonne Université, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Paris, France.
  • 6 Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taiwan.
  • 7 Pôle de Biologie, Hôpital Européen Georges Pompidou, France.
  • 8 Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Beijing, China.
  • 9 Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
  • 10 Department of Obstetrics and Gynecology, Department of Pharmacology, the Robert H. Lurie Comprehensive Cancer Center, Chemistry of Life Process Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois. yong.wan@northwestern.edu.
  • # Contributed equally.
PMID: 32938586 DOI: 10.1158/2159-8290.CD-20-0402
Abstract

Despite widespread utilization of immunotherapy, treating immune-cold tumors has proved to be a challenge. Here, we report that expression of the immune checkpoint molecule B7-H4 is prevalent among immune-cold triple-negative breast cancers (TNBC), where its expression inversely correlates with that of PD-L1. Glycosylation of B7-H4 interferes with its interaction/ubiquitination by AMFR, resulting in B7-H4 stabilization. B7-H4 expression inhibits doxorubicin-induced cell death through the suppression of eIF2α phosphorylation required for calreticulin exposure vis-à-vis the Cancer cells. NGI-1, which inhibits B7-H4 glycosylation causing its ubiquitination and subsequent degradation, improves the immunogenic properties of Cancer cells treated with doxorubicin, enhancing their phagocytosis by dendritic cells and their capacity to elicit CD8+ IFNγ-producing T-cell responses. In preclinical models of TNBC, a triple combination of NGI-1, camsirubicin (a noncardiotoxic doxorubicin analogue) and PD-L1 blockade was effective in reducing tumor growth. Collectively, our findings uncover a strategy for targeting the immunosuppressive molecule B7-H4. SIGNIFICANCE: This work unravels the regulation of B7-H4 stability by ubiquitination and glycosylation, which affects tumor immunogenicity, particularly regarding immune-cold breast cancers. The inhibition of B7-H4 glycosylation can be favorably combined with immunogenic chemotherapy and PD-L1 blockade to achieve superior immuno-infiltration of cold tumors, as well as improved tumor growth control.See related commentary by Pearce and Läubli, p. 1789.This article is highlighted in the In This Issue feature, p. 1775.

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