Expression of Immunosuppresive B7-H3 Ligand by Hormone-Treated Prostate Cancer Tumors and Metastases

Chavin, Grant; Sheinin, Yuri; Crispen, Paul L.; Boorjian, Stephen A.; Roth, Timothy J.; Rangel, Laureano J.; Blute, Michael L.; Sebo, Thomas J.; Tindall, D.; Kwon, Eugene D.; Karnes, R. Jeffrey

doi:10.1158/1078-0432.ccr-08-2262

Cited by 70 publications

(55 citation statements)

References 38 publications

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“…In other tumor entities, the frequency of tumor B7-H3-positive cases varied from 46% in RCC (22) to 96% in prostate cancer (46). As described by others (42,47), a low expression of both B7-H3 and B7-H4 with a score of 1 to 2 was detected in normal skin surrounding the benign lesions of the same patients ( Fig.…”

Section: Discussionsupporting

confidence: 58%

B7-H4 Expression in Human Melanoma: Its Association with Patients' Survival and Antitumor Immune Response

Quandt

Fiedler

Boettcher

et al. 2011

Clinical Cancer Research

129

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Purpose: Cancers have developed a number of strategies to escape immune responses including the differential expression of costimulatory molecules of the B7 family. B7-H3 and B7-H4 have recently been described in different tumor entities but the relevance for melanoma has not yet been studied so far.Experimental Design: Using immunohistochemistry, B7-H3 and B7-H4 expression was studied on 29 melanoma lesions. Survival curves and log-rank tests were used to test the association of protein expression with survival. Cell lines were evaluated for B7-H3 and B7-H4 expression by PCR and flow cytometry. Functional T-cell-tumor coculture assays were carried out with in vitro generated tumor transfectants.Results: B7-H3 and B7-H4 expression was detected in primary tumor lesions (29 of 29 and 28 of 29) and in metastases (28 of 29 and 26 of 29). The numbers of CD68 þ macrophages were significantly lower in patients with low B7-H4 expression, whereas CD8 þ T-cell infiltrates were independent of expression levels.Furthermore, a survival benefit for patients with B7-H4 low expressing melanoma was found, whereas B7-H3 was not associated with any clinical parameter. All 23 melanoma cell lines analyzed expressed B7-H3 and B7-H4 mRNA and protein, but B7-H4 was restricted to intracellular compartments. On silencing of B7-H3 by specific shRNA tumor-associated antigen-specific T cell responses were unaltered. Overexpression of B7-H4 on melanoma cells did not alter the cytotoxicity of different CD8 þ effector cells, but drastically inhibited cytokine production. Conclusions: Our study provides for the first time evidence of B7-H4 expression on melanoma cells as a mechanism controlling tumor immunity which is associated with patients' survival. Clin Cancer Res; 17(10); 3100-11. Ó2011 AACR.

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Section: Discussionsupporting

confidence: 58%

B7-H4 Expression in Human Melanoma: Its Association with Patients' Survival and Antitumor Immune Response

Quandt

Fiedler

Boettcher

et al. 2011

Clinical Cancer Research

129

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“…Several studies have suggested that B7-H3 is also present in certain types of human cancer and plays critical roles in carcinogenesis and tumor progression [6]. Up-regulation of B7-H3 occurs in a wide range of cancers, such as prostate cancer, lung cancer, colorectal carcinoma, pancreatic cancer, ovarian carcinoma and gastric cancer [7][8][9][10][11][12]. These observations demonstrate that overexpression of B7-H3 may indicate an aggressive biologic role in carcinogenesis.…”

Section: Introductionmentioning

confidence: 83%

Astragaloside IV Enhances Cisplatin Chemosensitivity in Non-Small Cell Lung Cancer Cells Through Inhibition of B7-H3

Liu

et al. 2016

Cell Physiol Biochem

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Background: Chemoresistance is a major obstacle to successful chemotherapy for human non-small cell lung cancer (NSCLC). Astragaloside IV, the component of Astragalus membranaceus, has been reported to exhibit anti-inflammation, anti-cancer and immunoregulatory properties. In the present study, we investigated the role of astragaloside IV in the chemoresistance to cisplatin in NSCLC cells. Methods: We established astragaloside IV-suppressed NSCLC cell lines including A549, HCC827, and NCI-H1299 and evaluated their sensitivity to cisplatin in vitro. In addition, we examined the mRNA and protein levels of B7-H3 in response to cisplatin-based chemotherapy. Results: We showed that high doses of astragaloside IV (10, 20, 40 ng/ml) inhibited NSCLC cell growth, whereas low concentrations of astragaloside IV (1, 2.5, 5 ng/ml) had no obvious cytotoxicity on cell viability. Moreover, combined treatment with astragaloside IV significantly increased chemosensitivity to cisplatin in NSCLC cells. On the molecular level, astragaloside IV co-treatment significantly inhibited the mRNA and protein levels of B7-H3 in the presence of cisplatin. In addition, ectopic expression of B7-H3 diminished the sensitization role of astragaloside IV in cellular responses to cisplatin in NSCLC cells. Conclusion: These results demonstrate that astragaloside IV enhances chemosensitivity to cisplatin via inhibition of B7-H3 and that treatment with astragaloside IV and inhibition of B7-H3 serve as potential therapeutic approach for lung cancer patients.

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“…In this article, we have described identification and characterization of a panel of mAbs with specificity for B7-H3, a protein overexpressed on many cancers, including prostate (15)(16)(17), renal (18), pancreatic (19,20), colorectal (21), non-small cell lung (NSCLC; ref. 22), ovarian (23), bladder (24), melanoma (25), and neuroectodermal (25) cancers and postulated to mediate immunomodulatory activity (26).…”

Section: Discussionmentioning

confidence: 99%

“…Reports suggesting a costimulatory role in immune modulation for B7-H3 (27) have been countered by a preponderance of evidence suggesting a tumor-supportive role in terms of immunologic escape (11,(32)(33)(34) and increased resistance to treatment (35). Overexpression of B7-H3 has been correlated with disease severity and poor outcome in a growing number of cancer types, including pathologic indicators of aggressiveness and negative clinical outcome in prostate cancer (15)(16)(17), increased grade and decreased T-lymphocyte infiltration in tumor nests and stroma in colorectal cancer (21), and a reduction in T-lymphocyte infiltrates in NSCLC (22). B7-H3 expression on tumor-associated vascular endothelia suggests additional roles for B7-H3 that favor tumor growth and progression, albeit by mechanism(s) not yet uncovered.…”

Section: Discussionmentioning

confidence: 99%

Development of an Fc-Enhanced Anti–B7-H3 Monoclonal Antibody with Potent Antitumor Activity

Loo

Alderson

Chen

et al. 2012

Clinical Cancer Research

223

171

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Purpose: The goal of this research was to harness a monoclonal antibody (mAb) discovery platform to identify cell-surface antigens highly expressed on cancer and develop, through Fc optimization, potent mAb therapies toward these tumor-specific antigens.Experimental Design: Fifty independent mAbs targeting the cell-surface immunoregulatory B7-H3 protein were obtained through independent intact cell-based immunizations using human tissue progenitor cells, cancer cell lines, or cell lines displaying cancer stem cell properties. Binding studies revealed this natively reactive B7-H3 mAb panel to bind a range of independent B7-H3 epitopes. Immunohistochemical analyses showed that a subset displayed strong reactivity to a broad range of human cancers while exhibiting limited binding to normal human tissues. A B7-H3 mAb displaying exquisite tumor/normal differential binding was selected for humanization and incorporation of an Fc domain modified to enhance effectormediated antitumor function via increased affinity for the activating receptor CD16A and decreased binding to the inhibitory receptor CD32B.Results: MGA271, the resulting engineered anti-B7-H3 mAb, mediates potent antibody-dependent cellular cytotoxicity against a broad range of tumor cell types. Furthermore, in human CD16A-bearing transgenic mice, MGA271 exhibited potent antitumor activity in B7-H3-expressing xenograft models of renal cell and bladder carcinoma. Toxicology studies carried out in cynomolgus monkeys revealed no significant test article-related safety findings.Conclusions: This data supports evaluation of MGA271 clinical utility in B7-H3-expressing cancer, while validating a combination of a nontarget biased approach of intact cell immunizations and immunohistochemistry to identify novel cancer antigens with Fc-based mAb engineering to enable potent antitumor activity.

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Expression of Immunosuppresive B7-H3 Ligand by Hormone-Treated Prostate Cancer Tumors and Metastases

Cited by 70 publications

References 38 publications

B7-H4 Expression in Human Melanoma: Its Association with Patients' Survival and Antitumor Immune Response

B7-H4 Expression in Human Melanoma: Its Association with Patients' Survival and Antitumor Immune Response

Astragaloside IV Enhances Cisplatin Chemosensitivity in Non-Small Cell Lung Cancer Cells Through Inhibition of B7-H3

Development of an Fc-Enhanced Anti–B7-H3 Monoclonal Antibody with Potent Antitumor Activity

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