Abstract 1678P
Background
Cancer-Associated Fibroblasts (CAFs) are a main component of the tumour microenvironment. Recent evidence suggests that high levels of CAFs correlate with poorer prognosis and a pro-tumorigenic microenvironment. The clinical relevance of CAF presence and the mechanisms by which they influence prognosis warrant further research.
Methods
We used publicly available RNAseq data from The Cancer Genome Atlas (TCGA), gene expression data from cancer-cell (CC)-CAF co-cultures of three different cell lines. Further in vitro validation experiments were performed on human Head and Neck cancer cell lines, patient derived CAFs and macrophages from healthy donors.
Results
We generated a gene signature that predicts the abundance of CAF/CC interaction in clinical RNAseq data from a meta-analysis of transcriptomic data derived from Cancer Cell (CC) and CAF co-cultures. This gene signature is predictive of worse overall survival in datasets of Squamous Cell Carcinoma (SCC) patients. CAF abundance and the co-culture signature are strongly correlated with RAS signalling. Mechanistically, we showed that AP-1 transcription factor genes are strongly up-regulated when CCs and CAFs are in close contact. Direct contact between CCs and CAFs upregulates the RAS pathway in both cell types through membrane bound growth factors and growth factor receptors, activating AP-1 activity. We also demonstrated that the RAS / AP-1 axis is used by CCs to induce secretion of pro-tumorigenic and immune-inhibitory cytokines from CAFs, enhancing migration of potentially immune-suppressive macrophages. Of note, patients with high expression of CC-CAF coculture genes show an immune-suppressive microenvironment. Importantly, treatment with ERK inhibitors is able to disrupt the activation of this pathway, blocking cytokine production and impairing macrophage migration.
Conclusions
In conclusion, we generated a gene signature predictive of overall survival in SCC patients, linked to cancer cell -CAF interaction and RAS signalling. This study reveals a novel mechanism of crosstalk between CCs and CAFs able to modulate the tumour immune microenvironment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
The Francis Crick Institute, Cancer Research UK, Wellcome Trust, UK Medical Research Council, NIHR Biomedical Research Centre at The Royal Marsden and the ICR.
Disclosure
G. Giangreco: Financial Interests, Institutional, Funding: MSD. K.J. Harrington: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Merck, MSD, Pfizer, Replimune, Oncolys, Vyriad, Idera; Financial Interests, Institutional, Other, Honoraria for lectures: Amgen, AstraZeneca, BMS, Boehringer Ingelheim; Financial Interests, Institutional, Advisory Board, Advisory board for CD47 assets: Arch Oncology; Financial Interests, Institutional, Advisory Board, Development of DDR assets: ARTIOS; Financial Interests, Institutional, Advisory Board, Development of exosomal STING agonist: Codiak; Financial Interests, Institutional, Advisory Board, Development of oncolytic adenovirus: PsiVac; Financial Interests, Institutional, Funding, Research: AstraZeneca, Boehringer Ingelheim, MSD; Financial Interests, Institutional, Funding, Development of oncolytic HSV platform: Replimune; Non-Financial Interests, Leadership Role, Chair of Steering Committee: ART NET; Non-Financial Interests, Other, Member of Global Steering Committee: MR - Linac. E. Sahai: Financial Interests, Personal, Advisory Board: Phenomic; Financial Interests, Personal and Institutional, Funding: MSD, GSK, AstraZeneca. All other authors have declared no conflicts of interest.