Mechanistic Characterization of Cancer-associated Fibroblast Depletion via an Antibody-Drug Conjugate Targeting Fibroblast Activation Protein.

Autor:	Gallant JP; Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Hintz HM; Department of Pharmacology, University of Minnesota School of Medicine, Minneapolis, Minnesota., Gunaratne GS; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Breneman MT; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Recchia EE; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., West JL; Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Ott KL; Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Heninger E; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Jackson AE; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Luo NY; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Rosenkrans ZT; Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Hernandez R; Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Zhao SG; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Lang JM; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Meimetis L; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Kosoff D; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; William S Middleton Memorial Veterans' Hospital, Madison, Wisconsin., LeBeau AM; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Jun 12; Vol. 4 (6), pp. 1481-1494.
DOI:	10.1158/2767-9764.CRC-24-0248
Abstrakt:	Cancer-associated fibroblasts (CAF) are a prominent cell type within the tumor microenvironment (TME) where they are known to promote cancer cell growth and survival, angiogenesis, drug resistance, and immunosuppression. The transmembrane prolyl protease fibroblast activation protein (FAP) is expressed on the surface of highly protumorigenic CAFs found in the stroma of nearly every cancer of epithelial origin. The widespread expression of FAP has made it an attractive therapeutic target based on the underlying hypothesis that eliminating protumorigenic CAFs will disrupt the cross-talk between components of TME resulting in cancer cell death and immune infiltration. This hypothesis, however, has never been directly proven. To eliminate FAP-expressing CAFs, we developed an antibody-drug conjugate using our anti-FAP antibody, huB12, coupled to a monomethyl auristatin E (huB12-MMAE) payload. After determining that huB12 was an effective targeting vector, we found that huB12-MMAE potently eliminated FAP-expressing cells as monocultures in vitro and significantly prolonged survival in vivo using a xenograft engineered to overexpress FAP. We investigated the effects of selectively eliminating CAFs using a layered, open microfluidic cell coculture platform, known as the Stacks. Analysis of mRNA and protein expression found that treatment with huB12-MMAE resulted in the increased secretion of the proinflammatory cytokines IL6 and IL8 by CAFs and an associated increase in expression of proinflammatory genes in cancer cells. We also detected increased secretion of CSF1, a cytokine involved in myeloid recruitment and differentiation. Our findings suggest that the mechanism of FAP-targeted therapies is through effects on the immune microenvironment and antitumor immune response. Significance: The direct elimination of FAP-expressing CAFs disrupts the cross-talk with cancer cells leading to a proinflammatory response and alterations in the immune microenvironment and antitumor immune response. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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