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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.

SUBMITTER: Song X

PROVIDER: S-EPMC7710601 | biostudies-literature |

REPOSITORIES: biostudies-literature

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