Duong Minh Ngoc, Cleret Aurore, Matera Eva-Laure, Chettab Kamel, Mathé Doriane, Valsesia-Wittmann Sandrine, Clémenceau Béatrice, Dumontet Charles
Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France.
Centre Léon Bérard, Pôle des sciences cliniques, Plateforme d'innovations en immunomonitoring et immunothérapie, 28 Promenade Léa et Napoléon Bullukian, 69008, Lyon, France.
Breast Cancer Res. 2015 Apr 24;17(1):57. doi: 10.1186/s13058-015-0569-0.
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.
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.
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.
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.
曲妥珠单抗已被用于治疗人表皮生长因子受体2（HER2）表达的乳腺癌，但其疗效受到原发性或获得性耐药的限制。尽管已经提出了许多机制来解释对曲妥珠单抗的耐药性，但关于肿瘤微环境的作用知之甚少。鉴于抗体依赖性细胞毒性（ADCC）在曲妥珠单抗抗肿瘤作用中的重要性以及乳腺中丰富的脂肪组织，我们研究了脂肪细胞对ADCC的影响。
我们建立了一种共培养系统来研究脂肪细胞在体外对ADCC的影响。结果在小鼠异种移植模型中进行了体内验证。
我们发现脂肪细胞以及前脂肪细胞通过分泌可溶性因子抑制HER2表达的乳腺癌细胞中曲妥珠单抗介导的ADCC。ADCC的抑制不是由于抗体的滴定或降解。我们发现脂肪细胞减少了自然杀伤细胞分泌干扰素-γ，但没有改变自然杀伤细胞的细胞毒性。用脂肪细胞条件培养基预孵育乳腺癌细胞降低了癌细胞对ADCC的敏感性。使用转录组学方法，我们发现癌细胞在暴露于脂肪细胞条件培养基时会发生重大变化。重要的是，在脂肪瘤旁边移植的乳腺肿瘤在小鼠异种移植模型中对曲妥珠单抗表现出耐药性。
总的来说，我们的研究结果强调了脂肪组织在曲妥珠单抗耐药中的重要性，并表明针对脂肪细胞与癌细胞相互作用的方法可能有助于使癌细胞对基于曲妥珠单抗的治疗敏感。
