Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response
Open Access
- 25 May 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Discovery
- Vol. 7 (1), 1-17
- https://doi.org/10.1038/s41421-021-00271-4
Abstract
The current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy.Keywords
Funding Information
- National Natural Science Foundation of China (81874048, 82002625, 81702938, 81770628, 81970553)
This publication has 64 references indexed in Scilit:
- Stromal biology and therapy in pancreatic cancer: a changing paradigmGut, 2015
- Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 TherapyClinical Cancer Research, 2014
- A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancerAnnals of Oncology, 2014
- Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal AdenocarcinomaCancer Cell, 2014
- Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced SurvivalCancer Cell, 2014
- Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced CancerThe New England Journal of Medicine, 2012
- Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in CancerThe New England Journal of Medicine, 2012
- Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal AdenocarcinomaCancer Cell, 2012
- Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolutionCell Cycle, 2010
- The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stromaCell Cycle, 2009