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 þ CAF subset of OSCC (n Z 104) was determined by CD68/actin alpha 2, smooth muscle (ACTA2þ; a-SMA) immunohistochemistry of serial sections. The CD68 þ a-SMA þ CAF subset was elevated from dysplasia to OSCC. Moreover, although both the tumor center and invasive front harbor an abundant CD68 þ CAF subset, patients with low-CD68 þ CAFs in the tumor center showed more recurrence after operation and shorter survival time, indicating the different function of CD68 þ 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 þ CAFs were associated with aberrant immune balance. A high proportion of tumor-supportive Tregs was found in patients with low-CD68 þ 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 þ fibroblasts participate in tumor initiation, but the low-CD68 þ CAF subset in OSCC is conducive to regulatory T-cell (Treg) recruitment in the tumor microenvironment and contribute to poor prognosis of OSCC patients.

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Purpose This was a retrospective analysis of the impact of the expression of p53 in the dys-plastic surgical margins of early oral squamous cell carcinoma (OSCC) (pT1-2, N0). Patients and methods Seventy-two patients with early oral squamous cell carcinoma (OSCC) were recruited. Margin characteristics were abstracted from the pathology report. Expression of p53 in dysplastic surgical margins was examined with the immunohistochemical method and was correlated with clinicopathological parameters and clinical outcomes. Results Patients with moderate/severe dysplasia had poor local relapse-free survival (RFS) compared to those with mild dysplasia. Thirty-two (44.4%) had at least one p53-positive margin, and there was a significant association between the expression of p53 and tumor recurrence ( P <0.001). p53-positive expression was correlated with RFS in patients with dysplastic margins, and its expression in moderate/severe dysplastic groups had a worse RFS than mild dysplastic groups. We also found that the grade of the dysplasia margin was not correlated with RFS in p53-negative groups. Multivariable analysis validated p53 expression in dysplastic surgical margins as an independent risk factor for recurrence. Conclusion Our results validated that p53 expression was an independent risk factor for early OSCC with dysplastic surgical margins. Additional therapy and close follow-up are needed for these patients.

Background Transforming growth factor‐β (TGF‐β) exerts its versatile function (oncogenic or tumor suppressive role) during the carcinogenesis in tumor microenvironment‐dependent manner. Considering the tumor heterogeneity, spatial and temporal distribution of TGF‐β in oral squamous cell carcinoma (OSCC) remained to be elucidated. Methods Formalin‐fixed, paraffin‐embedded sections derived from 73 patients with OSCC were immunostained, revealing expression patterns of TGF‐β, both at the regions of tumor center (TC) and invasive tumor front (ITF). Results The TGF‐β levels on tumor cells, fibroblast‐like cells (FLCs), and tumor‐infiltrating lymphocytes (TILs) were comparable and showed to be cell‐type‐independent manner. Although TC regions harbored less positive staining of TGF‐β than ITF in tumor cells (TGF‐βTumor cell) (89.0% vs 98.3%; P = 0.037), FLCs (TGF‐βFLC) (86.3% vs 96.6%; P = 0.043), and TILs (TGF‐βTIL) (83.6% vs 94.8%; P = 0.044), respectively, TGF‐β at TC regions, not at ITF, correlated to poor clinical outcomes. At TC regions, patients with high TGF‐βTumor cell had high recurrence rate, and patients with high TGF‐βTIL showed inferior worst pattern of invasion. Of note, high TGF‐βTumor cell at TC predicted shorter overall survival time, recurrence‐free survival, and disease‐free survival in patients with OSCC, whereas high TGF‐βTIL had no association with survival time. Cox regression analyses indicated that tumor cell‐derived TGF‐β at TC was an independent risk factor for survival outcome in patients with OSCC. Conclusions Tumor cell‐derived TGF‐β at TC regions, but not at ITF, could be a promising predictor for disease recurrence and poor prognosis of patients with OSCC.

Background MLL2 (mixed‐lineage leukemia 2) is recognized as an essential role in regulating histone 3 lysine 4 tri‐methylation (H3K4me3) in mammalian cells. It is frequently mutated to promote developmental diseases and tumor initiation. However, the expression pattern of MLL2 and its clinical significance for patients with early‐stage oral squamous cell carcinoma (OSCC) remain totally unknown. Methods Eighty‐five samples of primary early‐stage OSCC were enrolled in this retrospective study, and immunohistochemistry (IHC) was performed to detect the spatial pattern of MLL2. The diagnostic and prognostic value of MLL2 were assessed. Results MLL2 was widely expressed in tumor cells (TCs), fibroblast‐like cells (FLCs), and tumor‐infiltrating lymphocytes (TILs), both in tumor center and invasive tumor front, and showed no distributive heterogeneity. Moreover, regardless of cell types and microlocalization, patients with high expressed MLL2 had increased depth invasion of tumor (DOI). Besides, upregulation of MLL2TC and MLL2TIL in tumor center were both associated with poor differentiation, but showed no correlation with tumor growth with comparable Ki‐67 levels. Prognostic analysis indicated that early‐stage OSCC patients with enhanced MLL2TIL in invasive tumor front were susceptible to occur postoperative metastasis and recurrence. Indeed, patients with higher expressed MLL2TIL showed shorter overall survival (OS) and disease‐free survival (DFS), and MLL2TIL in invasive tumor front was an independent risk factor of DFS. Conclusion TIL‐derived MLL2 in invasive tumor front was an independent prognostic factor of DFS for early‐stage OSCC patients.

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