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Diminished CD68+ Cancer-Associated Fibroblast Subset Induces Regulatory T-Cell (Treg) Infiltration and Predicts Poor Prognosis of Oral Squamous Cell Carcinoma Patients
- Source :
- The American Journal of Pathology. 190:886-899
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Although cancer-associated fibroblasts (CAFs) are crucial stromal cells, characterizing their heterogeneity is far from complete. This study reports a novel subset of CAFs in oral squamous cell carcinoma (OSCC), which positively expressed CD68, the classic marker of macrophages. The spatial and temporal distribution of the CD68+ CAF subset of OSCC (n = 104) was determined by CD68/actin alpha 2, smooth muscle (ACTA2+; α-SMA) immunohistochemistry of serial sections. The CD68+ α-SMA+ CAF subset was elevated from dysplasia to OSCC. Moreover, although both the tumor center and invasive front harbor an abundant CD68+ CAF subset, patients with low-CD68+ CAFs in the tumor center showed more recurrence after operation and shorter survival time, indicating the different function of CD68+ CAFs in tumor initiation and progression. Functional analysis in the OSCC-CAF co-culture system found knockdown of CD68 did not change the phenotype of CAFs, tumor growth, or migration. Unexpectedly, low-CD68+ CAFs were associated with aberrant immune balance. A high proportion of tumor-supportive Tregs was found in patients with low-CD68+ CAFs. Mechanistically, knockdown of CD68 in CAFs contributed to the up-regulation of chemokine CCL17 and CCL22 of tumor cells to enhance Treg recruitment. Thus, up-regulated CD68+ fibroblasts participate in tumor initiation, but the low-CD68+ CAF subset in OSCC is conducive to regulatory T-cell (Treg) recruitment in the tumor microenvironment and contribute to poor prognosis of OSCC patients.
- Subjects :
- 0301 basic medicine
Tumor microenvironment
Stromal cell
biology
business.industry
Regulatory T cell
CD68
Tumor initiation
medicine.disease
Pathology and Forensic Medicine
stomatognathic diseases
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
medicine.anatomical_structure
030220 oncology & carcinogenesis
biology.protein
Cancer research
Carcinoma
Medicine
ACTA2
business
CCL22
Subjects
Details
- ISSN :
- 00029440
- Volume :
- 190
- Database :
- OpenAIRE
- Journal :
- The American Journal of Pathology
- Accession number :
- edsair.doi...........3ef6dd1754f99cfe4e3011ec8ff44cbe