The tumor immune microenvironment and its implications for clinical outcome in patients with oropharyngeal squamous cell carcinoma

Abstract

Background: We examined PD-L1 expression on tumor cells (TCs) and immune cells (ICs) and density of CD3 + and CD8 + tumor-infiltrating lymphocytes (TILs) in patients with oropharyngeal squamous cell carcinoma (OPSCC) and investigated their significance on clinicopathological characteristics and clinical outcomes. Methods: In a cohort of 65 patients treated by definitive intensity-modulated radiotherapy (IMRT) with curative intent, immunohistochemical analysis of PD-L1 expression on TCs and ICs, and TIL subtyping was performed on primary biopsy tumor tissues, followed by prognostic evaluation of these immune response-related parameters including classification into four tumor immune microenvironment (TIM) types. To evaluate HPV status, p16 immunohistochemistry was performed. Results: Densities of CD3 + and CD8 + TILs and PD-L1 expressions on TCs and ICs were significantly higher in p16+/HPV-mediated OPSCC. Patients with high densities of stromal CD8 + TILs displayed significantly better overall survival (OS) and progression-free survival (PFS). PD-L1 expression neither on tumor cells nor on immune cells affected survival outcomes. Distribution of TIM types based on the combination of PD-L1 expression on TCs and densities of CD8 + TILs is significantly different in p16+ compared with p16-OPSCC. In type III TIM (TC-PD-L1+/low CD8 + TIL density), significantly better OS was shown in p16+ group compared with p16-OPSCC. Conclusion: The prognostic and predictive role of tumor immune microenvironment was confirmed for patients with OPSCC. Combining HPV status with the evaluation of densities of CD8 + TILs and PD-L1 expression including TIM classification might be of high clinical interest and warrants further prospective evaluation.

Prognostic Significance of PD-L1 Expression In Patients With Primary Oropharyngeal Squamous Cell Carcinoma: A Meta-Analysis

“…The results revealed that positive PD-L1 expression was related to a significantly improved OS in patients with OPSCC (sHR = 0.63, 95% CI: 0.50-0.79). Differently, only seven articles provided HRs and 95% CIs for PFS in OPSCC ( 17 , 20 – 23 , 25 , 29 ). As depicted in Figure 2B , there was no significant heterogeneity among these 7 articles ( I 2 = 0%; p = 0.45).…”

“…The meta-analysis indicated that positive PD-L1 expression was related to greater PFS in patients with OPSCC (sHR = 0.62, 95% CI: 0.49–0.79). Finally, the association between PD-L1 expression and LRC was investigated in four studies ( 22 , 23 , 29 , 32 ) and a significant heterogeneity was not detected among them ( I 2 = 48%; p = 0.12) ( Figure 2C ). Although a significant relationship did not emerged, results showed that LRC was improved in OPSCC patients that were PD-L1 positive (sHR = 0.92, 95% CI: 0.55–1.53).…”

“…Nevertheless, the effect was greater and significant only in the group treated with up-front surgery (sHR = 0.34, 95% CI: 0.18–0.65). Unfortunately, data available for the present analysis was limited since only six studies were included ( 21 , 24 , 25 , 28 , 29 , 32 ).…”

The importin beta superfamily member RanBP17 exhibits a role in cell proliferation and is associated with improved survival of patients with HPV+ HNSCC

“…Furthermore, a highly significant correlation was seen between RanBP17 and CDKN2A , the gene encoding the cell cycle inhibitor and HPV surrogate marker p16 INK4A . Since HPV+ HNSCC are frequently associated with high levels of tumor infiltrating leukocytes (TILs) [ 24 ], the observed RanBP17 overexpression could also be derived from TILs present in the tumor. To further evaluate this aspect, we first looked into T-cell and B-cell marker expression levels and, consistent with previous reports, could observe significantly higher levels of these markers in HPV+ HNSCC compared with HPV- HNSCC (Supplementary Fig.…”

MicroRNAs in head and neck squamous cell carcinoma: a possible challenge as biomarkers, determinants for the choice of therapy and targets for personalized molecular therapies

“…Recent reports highlighted that HNSCC tumor microenvironment can regulate tumor response to radiation therapy throughout a crosstalk between tumor cells and the tumor microenvironment ( 190 ). Accordingly, it has been reported that miR-9 found enriched in HPV positive HNSCC exosome were able to enter into the macrophages inducing M1 macrophage polarization via downregulation of PPARδ, a member of the ligand-activated nuclear receptor superfamily involved in inflammation and innate immunity ( 191 ).…”