Abstract
Immunotherapy shows promising results and revolutionizes treatment of oral squamous cell carcinoma (OSCC). The immunologic microenvironment might have prognostic/predictive implications. Morphologic immunologic parameters (inflammatory infiltrate, stromal content, and budding activity [BA] [potentially indicating epithelial-mesenchymal transition]) were evaluated in 66 human primary therapy-naive OSCCs. Intraepithelial/stromal tumor-infiltrating lymphocytes (TILs; CD3+/CD4+/CD8+/CD4+FOXP3+/IL-17A+) were quantified, and ratios were calculated. HLA class I in tumor cells was evaluated immunohistochemically. mRNA in situ hybridization to detect IFN-γ was performed. Analysis was performed within invasive front (IF) and tumor center (TCe). Decreased HLA expression was associated with low TIL density, pronounced stromal content, and high BA; IFN-γ in TILs was correlated with high-density TILs; and IFN-γ in tumor cells was correlated with absence of BA (p < 0.05). Heterogeneity of parameters (TCe/IF) was rare. Low density of stromal CD4+FOXP3+ TILs within TCe and IF was identified as an independent prognostic factor for poor overall, disease-specific, and disease-free survival (p ≤ 0.011). Refining prognostication in OSCC with high-density CD4+FOXP3+ infiltrate within TCe and/or IF, high FOXP3:CD4 ratio was significantly correlated with favorable outcome in this subgroup. Furthermore, high-stromal CD8:CD4 ratio was found to be an independent favorable prognostic factor. In summary, immunologic parameters were closely intertwined. Morphologic correlates of epithelial-mesenchymal transition were associated with downregulation of HLA and decreased inflammation. Heterogeneity was infrequent. Low-density stromal CD4+FOXP3+ infiltrate within TCe and IF was an independent poor prognostic factor. Stratification of cases with high-density CD4+FOXP3+ TILs by FOXP3:CD4 ratio enables refinement of prognostication of this subgroup. CD8:CD4 ratio was identified as an independent prognostic factor.
Highlights
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The main focus of our present study was to further delineate the morphologic phenotype of the immunologic tumor–host interaction in oral squamous cell carcinoma (OSCC) as described in the cancer immunity cycle [15, 20], in particular to exactly describe the composition of the inflammatory infiltrate involved in cell-mediated immunity, composed by various subsets of T cells (CD3+ T cells; CD4+ TILs (CD4s)+ T cells; CD8+ TILs (CD8s)+ T killer cells; CD4+FOXP3+ TILs (FOXP3s)+ Tregs; IL-17A+ TILs (IL-17As)+ Th17 cells) and its association with HLA class I expression, IFN-g expression, and morphology, taking into account spatial heterogeneity of immunologic parameters
The immune cell infiltrate as well as HLA class I and IFN-g play an important role in head and neck squamous cell carcinoma [26, 27, 36, 38, 51, 52]
Summary
Our retrospective cohort comprised 66 patients with OSCC who underwent surgical resection of their primary tumors in curative intent between 2008 and 2012 at the Klinikum Rechts der Isar, Technical University of Munich, Germany following a standardized surgical procedure according the German guidelines for the treatment of OSCC [42]. TILs (CD3+, CD8+, CD4+, FOXP3+, IL-17A+) were evaluated, separating IF and TCe. The analysis of TIL subpopulations was performed in two ways: 1) Intraepithelial TILs: the tumor region of the respective cores showing the highest density of the particular TIL subpopulation was selected on lowpower magnification [34]. The analysis of TIL subpopulations was performed in two ways: 1) Intraepithelial TILs: the tumor region of the respective cores showing the highest density of the particular TIL subpopulation was selected on lowpower magnification [34] Within this region, the amount of intraepithelial CD3+ TILs (CD3i), intraepithelial CD8+ TILs (CD8i), and intraepithelial FOXP3+ TILs (FOXP3i) was scored manually by counting the absolute number of TILs within TC clusters of 100 TCs using high-power magnification (340; in analogy to Ref. 47). All statistical tests were performed at the exploratory two-sided 5% significance level
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