Presence of high-endothelial venules correlates with a favorable immune microenvironment in oral squamous cell carcinoma

• Published in: Modern pathology 2018-06, Vol.31 (6), p.910-922
• Main Authors: Wirsing, Anna Maria, Ervik, Ida Korsnes, Seppola, Marit, Uhlin-Hansen, Lars, Steigen, Sonja Eriksson, Hadler-Olsen, Elin
• Format: Article
• Language: English
• Subjects: 13/51; 38/1; 38/90; 631/67/327; 692/53/2422; Antitumor activity; Biomarkers, Tumor; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; CCL20 protein; CCL21 protein; CD20 antigen; CD3 antigen; CD4 antigen; Chemokines; Clinical medical disciplines: 750; CXCL12 protein; Cytokines; Endothelial Cells - immunology; Endothelial Cells - pathology; Gene expression; Humans; Immunohistochemistry; Immunomodulation; Inflammation; Klinisk medisinske fag: 750; Laboratory Medicine; Lymphocytes B; Lymphocytes T; Macrophages; Medical disciplines: 700; Medical prognosis; Medicine; Medicine & Public Health; Medisinske Fag: 700; Metastases; Mouth Neoplasms - immunology; Mouth Neoplasms - pathology; Neoplasm Staging; Oncology: 762; Onkologi: 762; Oral cancer; Oral carcinoma; Oral squamous cell carcinoma; Paraffin; Pathology; PD-1 protein; PD-L1 protein; Polymerase chain reaction; Prognosis; Retrospective Studies; Squamous cell carcinoma; Tumor cells; Tumor Microenvironment - immunology; Tumors; VDP; Venules - immunology; Venules - pathology
• ISSN: 0893-3952; 1530-0285; 1530-0285
• DOI: 10.1038/s41379-018-0019-5

Oral squamous cell carcinomas are associated with a poor prognosis, which may be partly due to functional impairment of the immune response. Lymphocyte recruitment to the tumor site is facilitated by high-endothelial venules, whereas expression of programmed-death ligand 1 (PD-L1) can impair T-cell function. Thus, we hypothesize that these factors are important in shaping the immune response in oral squamous cell carcinoma. In the present study, we characterized the immune infiltrate in formalin-fixed, paraffin-embedded tumor samples from 75 oral squamous cell carcinoma patients. We used immunohistochemistry to determine the distribution of immune cell subsets, high-endothelial venules, and PD-L1, as well as quantitative real-time polymerase chain reaction to assess the expression of inflammatory cytokines and chemokines associated with lymphocyte trafficking. Finally, we calculated correlations between the presence of immune cell subsets, the gene expression patterns, high-endothelial venules, PD-L1, and the clinicopathological parameters, including patient survival. The presence of high-endothelial venules correlated with increased number of CD3+ T cells and CD20+ B cells, higher levels of the chemokines CXCL12 and CCL21, and lower levels of CCL20, irrespective of the tumors' T stage. In univariate analysis, high levels of CD20+ B cells and CD68+ macrophages, positive high-endothelial venule status, and low T and N stages predicted longer patient survival. However, only the presence of high-endothelial venules and a low T stage were independent positive prognosticators. This indicates that high-endothelial venules are important mediators and a convenient marker of an antitumor immune response in oral squamous cell carcinoma. Our findings suggest that these vessels are a potential immunomodulatory target in this type of cancer. PD-L1 staining in tumor cells correlated with lower T stage, increased infiltration of CD4+ cells, and higher expression of several inflammation-related cytokines. Thus, oral squamous cell carcinomas rich in CD4+ cells may preferentially respond to PD-1/PD-L1 blockade therapy.