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

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.