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

Song X, Zhou Z, Li H, Xue Y, Lu X, Bahar I, Kepp O, Hung M-C, Kromer G, Wan Y. Pharmacologic Suppression of B7-H4 Glycosylation Restores Antitumor Immunity in Immune-Cold Breast Cancers. Cancer Discovery December 2020. doi:10.1158/2159-8290.CD-20-0402

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.

Publication Year: 
2020
Faculty Author: 
Publication Credits: 
Song X, Zhou Z, Li H, Xue Y, Lu X, Bahar I, Kepp O, Hung M-C, Kromer G, Wan Y.
Publication Download: 
AttachmentSize
PDF icon 1872.full_.pdf8.5 MB
^