Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity

Minh Ngoc Duong, Aurore Cleret, Eva-Laure Matera, Kamel Chettab, Doriane Mathé, Sandrine Valsesia-Wittmann, Béatrice Clémenceau, Charles Dumontet

Trastuzumab has been used in the treatment of human epidermal growth factor receptor 2 (HER2)-expressing breast cancer but its efficacy is limited due to de novo or acquired resistance. Although many mechanisms have been proposed to explain the resistance to trastuzumab, little is known concerning the role of the tumor microenvironment. Given the importance of antibody-dependent cell-mediated cytotoxicity (ADCC) in the antitumor effect of trastuzumab and the abundance of adipose tissue in breast, we investigated the impact of adipocytes on ADCC. We set up a co-culture system to study the effect of adipocytes on ADCC in vitro. The results were validated in vivo in xenograft mice. 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 a titration or a degradation of the antibody. We found that adipose cells decreased the secretion of interferon-gamma by natural killer cells, but did not alter their cytotoxicity. Pre-incubation 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 tumor grafted next to lipoma displayed resistance to trastuzumab in xenograft mouse models. 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.