Composition and Clinical Impact of the Immunologic Tumor Microenvironment in Oral Squamous Cell Carcinoma

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.

The presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different subsets serve as prognostic factors in advanced hypopharyngeal squamous cell carcinoma

“…Additionally, the current study also identified that a high CD8/CD4 ratio was associated with better DMFS and LRFS in UVA and was an independent prognostic factor for LRFS in MVA, although CD4 infiltrating T cells alone were not significantly correlated with survival implications. Consistent with our results, previous studies have reported that a high stromal CD8/CD4 ratio was found to be an independent favourable prognostic factor in oral squamous cell carcinoma, and one study revealed that the CD8/CD4 ratio was higher in cases without metastasis and in low-grade lesions [42,43]. Moreover, studies in lung cancer suggested that the CD8/ CD4 ratio in patients in the non-metastasis group was remarkably higher, and these patients had a significantly better overall survival rate than patients with a low CD8/ CD4 ratio [44,45].…”

The presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different subsets serve as prognostic factors in advanced hypopharyngeal squamous cell carcinoma

“…Additionally, the current study also identi ed that a high CD8/CD4 ratio was associated with better DMFS and LRFS in UVA and was an independent prognostic factor for LRFS in MVA, although CD4 in ltrating T cells alone were not signi cantly correlated with survival implications. Consistent with our results, previous studies have reported that a high stromal CD8/CD4 ratio was found to be an independent favourable prognostic factor in oral squamous cell carcinoma, and one study revealed that the CD8/CD4 ratio was higher in cases without metastasis and in low-grade lesions [42,43]. Moreover, studies in lung cancer suggested that the CD8/CD4 ratio in patients in the non-metastasis group was remarkably higher, and these patients had a signi cantly better overall survival rate than patients with a low CD8/CD4 ratio [44,45].…”

Development and validation of a seven‐immune‐feature‐based prognostic score for oral squamous cell carcinoma after curative resection

“…Consistent with our data, Boxberg et al . reported that low density of FOXP3 + TILs significantly correlated with inferior survival in OSCC . In addition, high FOXP3 + TILs tended to associate with increased survival in HPV‐ oral cancer, although p values did not reach statistical significance .…”

“…44,45 Consistent with our data, Boxberg et al reported that low density of FOXP3 + TILs significantly correlated with inferior survival in OSCC. 46 In addition, high FOXP3 + TILs tended to associate with increased survival in HPV-oral cancer, although p values did not reach statistical significance. 21 Some have proposed that the prognostic roles of FOXP3 + TILs are highly influenced by tumor sites, molecular subtypes and stages of tumor.…”