B7-h4 expression in human melanoma: its association with patients' survival and antitumor immune response

D Quandt, E Fiedler, D Boettcher, WC Marsch… - Clinical cancer …, 2011 - AACR
D Quandt, E Fiedler, D Boettcher, WC Marsch, B Seliger
Clinical cancer research, 2011AACR
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 …
Abstract
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+ macrophages were significantly lower in patients with low B7-H4 expression, whereas CD8+ 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+ 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. ©2011 AACR.
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