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Cancer Res. 2019 Aug 15. pii: canres.1246.2019. doi: 10.1158/0008-5472.CAN-19-1246. [Epub ahead of print]

Arming tumor-associated macrophages to reverse epithelial cancer progression.

Author information

1
Pathology, Moores Cancer Center, University of California, San Diego.
2
Department of Pathology, Moores UCSD Cancer Center, and Sanford Consortium of Regenerative Medicine, University of California, San Diego.
3
Department of Pathology, University of California, San Diego.
4
Department of Pathology, Moores UCSD Cancer Center, and Sanford Consortium of Regenerative Medicine, University of California, San Diego dcheresh@ucsd.edu.

Abstract

Tumor-associated macrophages (TAMs) are highly expressed within the tumor microenvironment of a wide range of cancers where they exert a pro-tumor phenotype by promoting tumor cell growth and suppressing anti-tumor immune function. Here, we showed that TAM accumulation in human and mouse tumors correlates with tumor cell expression of integrin αvβ3, a known driver of epithelial cancer progression and drug resistance. A monoclonal antibody targeting αvβ3 (LM609) exploited the co-enrichment of αvβ3 and TAMs to not only eradicate highly aggressive drug-resistant human lung and pancreas cancers in mice, but prevent the emergence of circulating tumor cells. Importantly, this anti-tumor activity in mice was eliminated following macrophage depletion. While LM609 had no direct effect on tumor cell viability, it engaged macrophages but not natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC) of αvβ3-expressing tumor cells despite their expression of the CD47 "don't eat me signal". In contrast to strategies designed to eliminate TAMs, these findings suggest that anti-αvβ3 represents a promising immunotherapeutic approach to redirect TAMs to serve as tumor killers for late-stage or drug-resistant cancers.

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