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

Xinwei Liu1, Yiwen Lu2, Jingying Huang2

  • 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Breast Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China.

Cancer Cell
|November 15, 2022
PubMed

Insights

Fibroblasts in breast cancer express Fc gamma receptors (FcγR), impacting therapeutic antibody effectiveness. Targeting VAV2 in these CD16+ fibroblasts may overcome drug resistance and improve treatment outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • Leukocyte Fc gamma receptor (FcγR)-mediated responses are crucial for therapeutic antibody efficacy.
  • The function of FcγRs in non-leukocyte cell types, particularly in cancer, remains largely unexplored.

Purpose of the Study:

  • To investigate the role of FcγRs in cancer-associated fibroblasts (CAFs).
  • To elucidate the mechanism by which FcγR-expressing CAFs contribute to therapeutic antibody resistance in HER2+ breast cancer.
  • To identify potential therapeutic targets to overcome this resistance.

Main Methods:

  • Identification and characterization of CD16 (FcγRIII)-expressing fibroblasts in human breast cancer tissue.
  • Analysis of the correlation between CD16+ fibroblast abundance and patient prognosis/treatment response.
  • Investigation of the signaling pathway activated by trastuzumab-FcγR interaction in fibroblasts.
  • Functional assays to assess the impact of CD16+ fibroblasts on extracellular matrix and drug delivery.
  • Targeting VAV2 to evaluate its role in fibroblast-mediated drug resistance.

Main Results:

  • A subset of fibroblasts in human breast cancer expresses CD16 (FcγRIII).
  • High abundance of CD16+ fibroblasts in HER2+ breast cancer patients correlates with poor prognosis and reduced response to trastuzumab.
  • Trastuzumab stimulation of CD16+ fibroblasts enhances extracellular matrix stiffness, impeding drug delivery.
  • The SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A pathway is activated, leading to increased contractile force and matrix production.
  • VAV2 is essential for CD16 function in fibroblasts and targeting it reverses fibroblast-induced desmoplasia.

Conclusions:

  • Fibroblast FcγR expression plays a significant role in mediating resistance to antibody-based therapies.
  • CD16+ fibroblasts contribute to drug resistance by altering the tumor microenvironment.
  • VAV2 is a critical mediator of this resistance mechanism and represents a promising therapeutic target to enhance antibody treatment efficacy.
Keywords:
Fcγ receptordesmoplasiadrug deliveryfibroblast

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