Arming Tumor-Associated Macrophages to Reverse Epithelial Cancer Progression.

ABSTRACT: Tumor-associated macrophages (TAM) are highly expressed within the tumor microenvironment of a wide range of cancers, where they exert a protumor phenotype by promoting tumor cell growth and suppressing antitumor immune function. Here, we show that TAM accumulation in human and mouse tumors correlates with tumor cell expression of integrin ?v?3, a known driver of epithelial cancer progression and drug resistance. A monoclonal antibody targeting ?v?3 (LM609) exploited the coenrichment of ?v?3 and TAMs to not only eradicate highly aggressive drug-resistant human lung and pancreas cancers in mice, but also to prevent the emergence of circulating tumor cells. Importantly, this antitumor activity in mice was eliminated following macrophage depletion. Although 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 ?v?3-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-?v?3 represents a promising immunotherapeutic approach to redirect TAMs to serve as tumor killers for late-stage or drug-resistant cancers. SIGNIFICANCE: Therapeutic antibodies are commonly engineered to optimize engagement of NK cells as effectors. In contrast, LM609 targets ?v?3 to suppress tumor progression and enhance drug sensitivity by exploiting TAMs to trigger ADCC.

SUBMITTER: Wettersten HI 

PROVIDER: S-EPMC6774806 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature