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Pharmacologic Inhibition of FGFR Modulates the Metastatic Immune Microenvironment and Promotes Response to Immune

Saeed S Akhand1, Zian Liu1, Stephen C Purdy1

  • 1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana.

Cancer Immunology Research
|October 23, 2020
PubMed

Insights

Fibroblast growth factor receptor (FGFR) inhibition with FIIN4 delayed metastatic breast cancer growth. Targeting FGFR enhances anti-tumor immunity by increasing CD8+ T-cell infiltration, improving immunotherapy response.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Immunotherapy efficacy in metastatic breast cancer is limited by low tumor-infiltrating lymphocytes.
  • Fibroblast growth factor receptor (FGFR) signaling plays a role in cancer progression and immune evasion.

Purpose of the Study:

  • To investigate the impact of FGFR inhibition on the tumor immune microenvironment and metastatic breast cancer growth.
  • To evaluate the combination of FGFR inhibitors with immune checkpoint blockade.

Main Methods:

  • Utilized syngeneic models of metastatic breast cancer and systemic tumor dormancy.
  • Administered FIIN4, a covalent FGFR inhibitor, as monotherapy and in combination with anti-PD-L1.
  • Assessed immune cell infiltration (CD8+ lymphocytes, myeloid suppressor cells) and tumor growth.
  • Investigated the role of FGFR1 in lymphocyte trafficking and CXCL16 expression.

Main Results:

  • FIIN4 treatment significantly delayed pulmonary metastases growth and enhanced tumor immunogenicity.
  • FGFR inhibition increased CD8+ T-cell infiltration and decreased myeloid suppressor cells in the tumor microenvironment.
  • Genetic FGFR1 depletion mimicked FIIN4 effects, indicating FGFR signaling influences lymphocyte trafficking.
  • Sequential dosing of FIIN4 followed by anti-PD-L1 overcame initial combination therapy failures.

Conclusions:

  • Targeting FGFR with FIIN4 can enhance antitumor immunity and delay metastatic breast cancer progression.
  • Sequential administration of FGFR inhibitors and immunotherapy represents a promising strategy for improving treatment outcomes.
  • Further research is warranted to explore FGFR inhibition in combination with immunotherapy for metastatic breast cancer.

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