Abstract
BackgroundCancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects.MethodsWe performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB).ResultsWhereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity. Gene expression profiling indeed showed that nintedanib influenced antitumour immunity and fibrosis. Tumoural infiltration of CD8+ T cells and granzyme B production were increased by nintedanib, and its antitumour activity was attenuated by antibody-mediated depletion of these cells, indicating that nintedanib suppressed tumour growth in a CD8+ T cell-dependent manner. Moreover, nintedanib inhibited the proliferation and activation of fibroblasts. Finally, the combination of nintedanib with ICB showed enhanced antitumour efficacy in B16-F10 tumour-bearing mice.ConclusionsOur results suggest that nintedanib targeted CAFs and thereby attenuated the immunosuppressive nature of the TME and promoted the intratumoural accumulation and activation of CD8+ T cells, with these effects contributing to enhanced antitumour activity in combination with ICB.
Highlights
Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects
Immunoblot analysis revealed that VEGF receptor (VEGFR)-2, platelet-derived growth factor receptor (PDGFR)-α and fibroblast growth factor receptor (FGFR)-2 were essentially undetectable in these cells (Fig. 1a)
Nintedanib did attenuate the viability of H1703 human lung squamous cell carcinoma cells (Fig. 1b), which served as a positive control on the basis of the previous detection of FGFR1 and PDGFRA amplification in these cells[22,23] and of our finding that they express PDGFR-α and FGFR-2 (Supplementary Fig. 2)
Summary
Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects. The TME ( referred to as the tumour stroma) comprises all the noncancer cell components of a tumour, including fibroblasts, myeloid-derived suppressor cells, macrophages, lymphocytes, extracellular matrix (ECM) and intertwined blood vessels formed by endothelial cells and pericytes.[2,3,4] Such cancer-associated stromal cells, together with inhibitory cytokines in the TME, give rise to an immunosuppressive niche in which tumour cells are protected from antitumour immune cells and thereby promote failure of ICB therapy.[1] Targeting of the TME is a promising approach to increase the efficacy of ICB.[1] inhibition of vascular endothelial growth factor (VEGF), which acts on endothelial cells to stimulate angiogenesis and limits immune cell activity, was found to be associated with an improved response to ICB therapy in renal cell carcinoma.[5]
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