中山大学Shicheng Su团队近期取得重要工作进展，他们研究发现通过抑制VAV2可以逆转由CD16⁺成纤维细胞导致的曲妥珠单抗耐药微环境。相关论文2022年11月14日在线发表于《癌细胞》杂志上。

研究人员鉴定出人类乳腺癌中表达CD16（FcγRIII）的成纤维细胞亚群。HER2⁺乳腺癌患者中这些细胞的丰富与不良预后和曲妥珠单抗的反应有关。在曲妥珠单抗刺激下，CD16⁺成纤维细胞通过增强细胞外基质硬度来减少药物递送。曲妥珠单抗和CD16之间的相互作用激活细胞内SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A通路，导致收缩力和基质生成增加。靶向Rho家族鸟嘌呤核苷酸交换因子VAV2（其对成纤维细胞而非白细胞中CD16的功能必不可少）可逆转CD16⁺成纤维细胞引起的结缔组织增生。

总之，这一研究揭示成纤维细胞FcγR在耐药性中的作用，并表明VAV2是增强抗体治疗效果的一个有吸引力的靶点。

据介绍，白细胞Fcγ受体（FcγR）介导的应答对治疗性抗体的疗效很重要。然而，关于FcγR在其他细胞类型中的作用还知之甚少。

附：英文原文

Title: CD16+ fibroblasts foster a trastuzumab-refractory microenvironment that is reversed by VAV2 inhibition

Author: Xinwei Liu, Yiwen Lu, Jingying Huang, Yue Xing, Huiqi Dai, Liling Zhu, Shunrong Li, Jingwei Feng, Boxuan Zhou, Jiaqian Li, Qidong Xia, Jiang Li, Min Huang, Yuanting Gu, Shicheng Su

Issue&Volume: 2022/11/14

Abstract: The leukocyte Fcγ receptor (FcγR)-mediated response is important for the efficacyof therapeutic antibodies; however, little is known about the role of FcγRs in othercell types. Here we identify a subset of fibroblasts in human breast cancer that expressCD16 (FcγRIII). An abundance of these cells in HER2+ breast cancer patients is associated with poor prognosis and response to trastuzumab.Functionally, upon trastuzumab stimulation, CD16+ fibroblasts reduce drug delivery by enhancing extracellular matrix stiffness. Interactionbetween trastuzumab and CD16 activates the intracellular SYK-VAV2-RhoA-ROCK-MLC2-MRTF-Apathway, leading to elevated contractile force and matrix production. Targeting ofa Rho family guanine nucleotide exchange factor, VAV2, which is indispensable forthe function of CD16 in fibroblasts rather than leukocytes, reverses desmoplasia provokedby CD16+ fibroblasts. Collectively, our study reveals a role for the fibroblast FcγR in drugresistance, and suggests that VAV2 is an attractive target to augment the effectsof antibody treatments.

DOI: 10.1016/j.ccell.2022.10.015

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00506-2