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

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.

• Authors: Xinxin Song, Zhuan Zhou, Hongchun Li, Yifan Xue, Xinghua Lu, Ivet Bahar, Oliver Kepp, Mien-Chie Hung, Guido Kroemer, Yong Wan
• Journal: Cancer discovery (Cancer Discov) Vol. 10 Issue 12 Pg. 1872-1893 (12 2020) ISSN: 2159-8290 [Electronic] United States
• PMID: 32938586 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• B7-H1 Antigen
• Benzamides
• CD274 protein, human
• CID2519269
• Sulfonamides
• V-Set Domain-Containing T-Cell Activation Inhibitor 1
• VTCN1 protein, human
• Doxorubicin

Topics

• Animals
• B7-H1 Antigen (antagonists & inhibitors, immunology)
• Benzamides (pharmacology)
• Cell Line, Tumor
• Doxorubicin (pharmacology)
• Female
• Glycosylation
• HEK293 Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Sulfonamides (pharmacology)
• Triple Negative Breast Neoplasms (drug therapy, immunology)
• Ubiquitination
• V-Set Domain-Containing T-Cell Activation Inhibitor 1 (antagonists & inhibitors, immunology)