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The anti-B7-H4 checkpoint synergizes trastuzumab treatment to promote phagocytosis and eradicate breast cancer.

ABSTRACT: Trastuzumab is a humanized mAb used to treat HER2-overexpressing breast cancer; however its mechanisms remain to be fully elucidated. Previous studies suggest a role for immunity in mediating trastuzumab-specific antitumor effects. This study evaluated the role(s) of trastuzumab and other antibodies on macrophage activation and Ab-dependent cell-mediated phagocytosis (ADCP) of HER2+ breast cancer cells in vitro and in vivo. We employed orthotopic implantation of HER2+ murine breast cancer (BC) cells in immunocompetent mouse models, a human HER2+ BC xenograft in an immune humanized mouse model, and human PDXs involving adoptive transfer of autologous macrophages to simulate an endogenous mammary tumor-immune microenvironment. Our study demonstrated that trastuzumab greatly and consistently increased macrophage frequency and tumor-cell phagocytosis, and that concurrent knockdown of B7-H4 by a neutralizing antibody increased immune cell infiltration and promoted an antitumor phenotype. Furthermore, neoadjuvant trastuzumab therapy significantly upregulated B7-H4 in the cancer-infiltrating macrophages of HER2+ BC patients, which predicted poor trastuzumab response. We suggest that strategies to specifically enhance ADCP activity might be critical to overcoming resistance to HER2 mAb therapies by inhibiting tumor growth and potentially enhance antigen presentation. Furthermore, these results advance the understanding of macrophage plasticity by uncovering a dual role for ADCP in macrophages involving elimination of tumors by engulfing cancer cells while causing a concomitant undesired effect by upregulating immunosuppressive checkpoints.

SUBMITTER: Hu X

PROVIDER: S-EPMC7509589 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The anti-B7-H4 checkpoint synergizes trastuzumab treatment to promote phagocytosis and eradicate breast cancer.

Hu Xiaochen X Liu Yiwen Y Zhang Xiusen X Kong Dejiu D Kong Jinyu J Zhao Di D Guo Yibo Y Sun Lingyun L Chu Luoyi L Liu Shupei S Hou Xurong X Ren Feng F Zhao Ying Y Lu Chengbiao C Zhai Desheng D Yuan Xiang X

Neoplasia (New York, N.Y.) 20200920 11

Trastuzumab is a humanized mAb used to treat HER2-overexpressing breast cancer; however its mechanisms remain to be fully elucidated. Previous studies suggest a role for immunity in mediating trastuzumab-specific antitumor effects. This study evaluated the role(s) of trastuzumab and other antibodies on macrophage activation and Ab-dependent cell-mediated phagocytosis (ADCP) of HER2<sup>+</sup> breast cancer cells in vitro and in vivo. We employed orthotopic implantation of HER2<sup>+</sup> murin ...[more]

PMID: 32966956

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Project description:BACKGROUND: B7-H4, a co-inhibitory molecule of the B7 family, can restrain T cell proliferation, cytokine secretion and the development of cytotoxicity. B7-H4 is expressed in tumor tissues at a higher level than in normal tissues, and has a potential effect to protect tumors from anti-tumor immune responses. This case-control study was carried out to determine the potential influences of B7-H4 gene polymorphisms on the susceptibility and progression of breast cancer in Han women of Northeast China. METHODS: We genotyped three B7-H4 variants (rs10754339, rs10801935 and rs3738414) and tagged all common haplotypes (frequency greater than or equal to 1%) in a Chinese population consisting of 500 breast cancer cases and 504 control individuals matched for age. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to determine the genotypes. RESULTS: Our data indicated that, compared with the common genotype and allele of each SNP, the rs10754339 AG genotype and G allele showed a significantly increased risk of breast cancer (OR = 1.455, 95% CI 1.119-1.892; OR = 1.325, 95% CI 1.073-1.637, respectively). The rs10801935 CC genotype, the rs3738414 AA genotype and the rs3738414 A allele were associated with a significantly decreased risk of breast cancer (OR = 0.328, 95% CI 0.145-0.739; OR = 0.412, 95% CI 0.203-0.835; OR = 0.698, 95% CI 0.564-0.864, respectively). Additionally, the rs10754339 GG genotype was significantly associated with lymph node metastasis and PR status, and the G allele and the AG genotype were respectively associated with lymph node metastasis and ER status. In haplotype analysis, we observed that compared with the AAG haplotype, the AAA haplotype showed a significantly decreased risk of breast cancer (OR = 0.689, 95% CI 0.539-0.881), but the GAG haplotype was associated with a significantly increased risk of breast cancer (OR = 1.511, 95% CI 1.125-2.031). And the AAA and the GCG haplotypes also respectively have significant influences on tumor size and ER status. CONCLUSION: These results suggest that B7-H4 gene polymorphism may contribute to the sporadic breast cancer risk and prognosis in Chinese Han women.

Project description:BackgroundThe expression of the immunoregulatory protein B7-H4 has been reported in many types of cancer, including breast cancer. However, its role in triple-negative breast cancer (TNBC), especially its correlation with patients' prognosis and chemoresistance remains unclear.MethodsThe expression of B7-H4 in TNBC tissues and cell lines were measured with Real-Time PCR and western blotting. 65 cases of TNBC tissue samples and adjacent non-tumor tissue samples were analyzed by immunochemistry to demonstrate the correlation between the B7-H4 expression and clinicopathological characteristics. In vitro studies assessed mAb MIH43 alone and in combination with transfecting B7-H4 siRNA on the growth of chemosensitive and chemoresistant TNBC cell lines by CCK-8 and apoptotic enzyme-linked immunosorbent assay (ELISA).ResultsB7-H4 expression was detected positive in 59 of 65 (90.8%) different stage TNBC patients, especially in the samples of recurrence TNBC patients after receiving neoadjuvant chemotherapy treatment. Survival curves showed that patients with B7-H4 overexpression had significantly shorter survival and recurrence time than those with low B7-H4 expression (p?<?0.005). Univariate and multivariate COX regression analysis demonstrated that B7-H4 was an independent predictor for advanced tumor stage. The monoclonal antibody of B7-H4 has the potential anti-proliferative effects on inhibiting the chemoresistant TNBC cell lines and increasing the sensitivity of TNBC cell lines to doxorubicin, paclitaxel or carboplatin. RNAi-mediated silencing of B7-H4 in TNBC cells enhanced drug-induced apoptosis via inhibiting PTEN/PI3K/AKT pathway, whereas reexpression of B7-H4 in B7-H4 knockdown and low B7-H4 expressing cells increased the phosphorylation of PI3K and AKT along with restoration of PETN expression.ConclusionsOur data show that B7-H4 is a biomarker indicative of a poor prognosis in TNBC patients and at least partially downregulated in chemoresistance via PTEN/PI3K/AKT pathway. Targeting B7-H4 might provide an attractive therapeutic approach specifically for TNBC patients.

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The anti-B7-H4 checkpoint synergizes trastuzumab treatment to promote phagocytosis and eradicate breast cancer.

Publications

The anti-B7-H4 checkpoint synergizes trastuzumab treatment to promote phagocytosis and eradicate breast cancer.

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