Diminished CD68+ Cancer-Associated Fibroblast Subset Induces Regulatory T-Cell (Treg) Infiltration and Predicts Poor Prognosis of Oral Squamous Cell Carcinoma Patients
Xingxing Zhao, Liang Ding, Zhanyi Lu, Xiaofeng Huang, Yue Jing, Yang Yan, Sheng Chen, Qingang Hu, Yanhong Ni
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 Z 104) was determined by CD68/actin alpha 2, smooth muscle (ACTA2; a-SMA) immunohistochemistry of serial sections. The CD68 a-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 OSCCeCAF 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.