Journal article
Pharmacologic Inhibition of FGFR Modulates the Metastatic Immune Microenvironment and Promotes Response to Immune Checkpoint Blockade
Cancer immunology research, Vol.8(12), pp.1542-1553
12/2020
DOI: 10.1158/2326-6066.CIR-20-0235
PMCID: 7710538
PMID: 33093218
Abstract
The effectiveness of immunotherapy as a treatment for metastatic breast cancer is limited due to low numbers of infiltrating lymphocytes in metastatic lesions. Herein, we demonstrated that adjuvant therapy using FIIN4, a covalent inhibitor of fibroblast growth factor receptor (FGFR), dramatically delayed the growth of pulmonary metastases in syngeneic models of metastatic breast cancer. In addition, we demonstrated in a syngeneic model of systemic tumor dormancy that targeting of FGFR enhanced the immunogenicity of the pulmonary tumor microenvironment through increased infiltration of CD8
lymphocytes and reduced presence of myeloid suppressor cells. Similar impacts on immune cell infiltration were observed upon genetic depletion of FGFR1 in tumor cells, which suggested a direct influence of FGFR signaling on lymphocyte trafficking. Suppression of CD8
lymphocyte infiltration was consistent with FGFR-mediated inhibition of the T-cell chemoattractant CXCL16. Initial attempts to concomitantly administer FIIN4 with immune checkpoint blockade failed due to inhibition of immune-mediated tumor cell killing via blockade of T-cell receptor signaling by FIIN4. However, this was overcome by using a sequential dosing protocol that consisted of FIIN4 treatment followed by anti-PD-L1. These data illustrate the complexities of combining kinase inhibitors with immunotherapy and provide support for further assessment of FGFR targeting as an approach to enhance antitumor immunity and improve immunotherapy response rates in patients with metastatic breast cancer.
Details
- Title: Subtitle
- Pharmacologic Inhibition of FGFR Modulates the Metastatic Immune Microenvironment and Promotes Response to Immune Checkpoint Blockade
- Creators
- Saeed S Akhand - Purdue University West LafayetteZian Liu - Purdue University West LafayetteStephen C Purdy - Purdue University West LafayetteAmmara Abdullah - Purdue University West LafayetteHang Lin - Purdue University West LafayetteGregory M Cresswell - Purdue University West LafayetteTimothy L Ratliff - Purdue University West LafayetteMichael Wendt - Purdue University West Lafayette
- Resource Type
- Journal article
- Publication Details
- Cancer immunology research, Vol.8(12), pp.1542-1553
- DOI
- 10.1158/2326-6066.CIR-20-0235
- PMID
- 33093218
- PMCID
- 7710538
- ISSN
- 2326-6066
- eISSN
- 2326-6074
- Grant note
- R01 CA232589 / NCI NIH HHS R01 CA207751 / NCI NIH HHS R21 AA026675 / NIAAA NIH HHS P30 CA023168 / NCI NIH HHS
- Language
- English
- Date published
- 12/2020
- Academic Unit
- Urology; Internal Medicine
- Record Identifier
- 9984460333002771
Metrics
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