Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts
Open Access
- 10 December 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 124 (5), 914-924
- https://doi.org/10.1038/s41416-020-01201-z
Abstract
Background Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects. Methods We 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). Results Whereas 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. Conclusions Our 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.Keywords
Funding Information
- Nippon Boehringer Ingelheim
This publication has 36 references indexed in Scilit:
- Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?Asco Educational Book, 2019
- The lung microenvironment: an important regulator of tumour growth and metastasisNature Reviews Cancer, 2018
- Turning foes to friends: targeting cancer-associated fibroblastsNature Reviews Drug Discovery, 2018
- Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinomaNature Communications, 2016
- FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 SignalingCancer Research, 2016
- Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progressionNature Medicine, 2016
- Immunological hallmarks of stromal cells in the tumour microenvironmentNature Reviews Immunology, 2015
- Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trialThe Lancet Oncology, 2014
- Mechanisms of fibrosis: therapeutic translation for fibrotic diseaseNature Medicine, 2012
- Friends or foes — bipolar effects of the tumour stroma in cancerNature Reviews Cancer, 2004