Pharmacologic suppression of B7-H4 glycosylation restores antitumor immunity in immune-cold breast cancers

Xinxin Song, Zhuan Zhou, Hongchun Li, Yifan Xue, Xinghua Lu, Ivet Bahar, Oliver Kepp, Mien Chie Hung, Guido Kroemer, Yong Wan

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 doxorubicininduced cell death through the suppression of eIF2 a 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 + IFN γ -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 fi ndings 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-infi ltration of cold tumors, as well as improved tumor growth control.

Original languageEnglish (US)
Pages (from-to)1872-1894
Number of pages23
JournalCancer discovery
Volume10
Issue number12
DOIs
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Oncology

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