Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity
Abstract
Introduction: Trastuzumab has been used in the treatment of human epidermal growth factor receptor 2 (HER2)-
expressing breast cancer, but its efficacy is limited by de novo or acquired resistance. Although many mechanisms
have been proposed to explain resistance to trastuzumab, little is known concerning the role of the tumor
microenvironment. Given the importance of antibody-dependent cellular cytotoxicity (ADCC) in the antitumor effect
of trastuzumab and the abundance of adipose tissue in the breast, we investigated the impact of adipocytes
on ADCC.
Methods: We set up a coculture system to study the effect of adipocytes on ADCC in vitro. The results were
validated in vivo in a mouse xenograft model.
Results: We found that adipocytes, as well as preadipocytes, inhibited trastuzumab-mediated ADCC in HER2-
expressing breast cancer cells via the secretion of soluble factors. The inhibition of ADCC was not due to titration or
degradation of the antibody. We found that adipose cells decreased the secretion of interferon-γ by natural killer
cells, but did not alter natural killer cells’ cytotoxicity. Preincubation of breast cancer cells with the conditioned
medium derived from adipocytes reduced the sensitivity of cancer cells to ADCC. Using a transcriptomic approach,
we found that cancer cells undergo major modifications when exposed to adipocyte-conditioned medium.
Importantly, breast tumors grafted next to lipomas displayed resistance to trastuzumab in mouse xenograft models.
Conclusions: Collectively, our findings underline the importance of adipose tissue in the resistance to trastuzumab
and suggest that approaches targeting the adipocyte–cancer cell crosstalk may help sensitize cancer cells to
trastuzumab-based therapy.
Domains
Cancer
Origin : Publisher files allowed on an open archive
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