Novel recombinant human b7-h4 antibodies overcome tumoral immune escape to potentiate T-cell antitumor responses.

Details

Serval ID
serval:BIB_74E16544B1E9
Type
Article: article from journal or magazin.
Collection
Publications
Title
Novel recombinant human b7-h4 antibodies overcome tumoral immune escape to potentiate T-cell antitumor responses.
Journal
Cancer research
Author(s)
Dangaj D., Lanitis E., Zhao A., Joshi S., Cheng Y., Sandaltzopoulos R., Ra H.J., Danet-Desnoyers G., Powell D.J., Scholler N.
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Publication state
Published
Issued date
01/08/2013
Peer-reviewed
Oui
Volume
73
Number
15
Pages
4820-4829
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
B7-H4 (VTCN1, B7x, B7s) is a ligand for inhibitory coreceptors on T cells implicated in antigenic tolerization. B7-H4 is expressed by tumor cells and tumor-associated macrophages (TAM), but its potential contributions to tumoral immune escape and therapeutic targeting have been less studied. To interrogate B7-H4 expression on tumor cells, we analyzed fresh primary ovarian cancer cells collected from patient ascites and solid tumors, and established cell lines before and after in vivo passaging. B7-H4 expression was detected on the surface of all fresh primary human tumors and tumor xenotransplants, but not on most established cell lines, and B7-H4 was lost rapidly by tumor xenograft cells after short-term in vitro culture. These results indicated an in vivo requirement for B7-H4 induction and defined conditions for targeting studies. To generate anti-B7-H4-targeting reagents, we isolated antibodies by differential cell screening of a yeast-display single-chain fragments variable (scFv) library derived from patients with ovarian cancer. We identified anti-B7-H4 scFv that reversed in vitro inhibition of CD3-stimulated T cells by B7-H4 protein. Notably, these reagents rescued tumor antigen-specific T-cell activation, which was otherwise inhibited by coculture with antigen-loaded B7-H4+ APCs, B7-H4+ tumor cells, or B7-H4- tumor cells mixed with B7-H4+ TAMs; peritoneal administration of anti-B7-H4 scFv delayed the growth of established tumors. Together, our findings showed that cell surface expression of B7-H4 occurs only in tumors in vivo and that antibody binding of B7-H4 could restore antitumor T-cell responses. We suggest that blocking of B7-H4/B7-H4 ligand interactions may represent a feasible therapeutic strategy for ovarian cancer.
Keywords
Animals, Ascites, Cell Line, Tumor, Female, Flow Cytometry, Humans, Lymphocyte Activation/immunology, Macrophages/immunology, Mice, Ovarian Neoplasms/immunology, Ovarian Neoplasms/metabolism, Ovarian Neoplasms/pathology, Single-Chain Antibodies/immunology, T-Lymphocytes/immunology, Tumor Escape/immunology, V-Set Domain-Containing T-Cell Activation Inhibitor 1/immunology, V-Set Domain-Containing T-Cell Activation Inhibitor 1/metabolism, Xenograft Model Antitumor Assays
Pubmed
Web of science
Create date
04/04/2022 18:09
Last modification date
05/04/2022 6:36
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