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

• DOI: 10.1016/j.ccell.2022.10.015
• Publication Date: 2022-11-14T15:47:23Z
• Authors: 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
• Keywords: 0303 health sciences; 03 medical and health sciences; Receptor, ErbB-2; Receptors, IgG; Tumor Microenvironment; Humans; Female; Breast Neoplasms; Trastuzumab; Fibroblasts; Proto-Oncogene Proteins c-vav; Extracellular Matrix

The leukocyte Fcγ receptor (FcγR)-mediated response is important for the efficacy of therapeutic antibodies; however, little is known about the role of FcγRs in other cell types. Here we identify a subset of fibroblasts in human breast cancer that express CD16 (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. Interaction between trastuzumab and CD16 activates the intracellular SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A pathway, leading to elevated contractile force and matrix production. Targeting of a Rho family guanine nucleotide exchange factor, VAV2, which is indispensable for the function of CD16 in fibroblasts rather than leukocytes, reverses desmoplasia provoked by CD16+ fibroblasts. Collectively, our study reveals a role for the fibroblast FcγR in drug resistance, and suggests that VAV2 is an attractive target to augment the effects of antibody treatments.