Prognostic Role of CD68(+) and CD163(+) Tumour-Associated Macrophages and PD-L1 Expression in Oral Squamous Cell Carcinoma: A Meta-Analysis.

Background: Oral squamous cell carcinoma (OSCC) is a common malignant cancer in humans. An abundance of tumour associated macrophages (TAMs) create an immunosuppressive tumour microenvironment (TME). TAM markers (CD163 and CD68) are seen to serve as prognostic factors in OSCC. PD-L1 has seen to widely modulate the TME but its prognostic significance remains controversial. The aim of this meta-analysis is to evaluate the prognostic role of CD163+, CD68+ TAMs and PD-L1 in OSCC patients. Methods: Searches in PubMed, Scopus and Web of Science were performed; 12 studies were included in this meta-analysis. Quality assessment of included studies was performed according to REMARK guidelines. Risk of bias across studies was investigated according to the rate of heterogeneity. Meta-analysis was performed to investigate the association of all three biomarkers with overall survival (OS). Results: High expression of CD163+ TAMs were associated with poor overall survival (HR = 2.64; 95% Cl: [1.65, 4.23]; p < 0.0001). Additionally, high stromal expression of CD163+ TAMs correlated with poor overall survival (HR = 3.56; 95% Cl: [2.33, 5.44]; p < 0.00001). Conversely, high CD68 and PD-L1 expression was not associated with overall survival (HR = 1.26; 95% Cl: [0.76, 2.07]; p = 0.37) (HR = 0.64; 95% Cl: [0.35, 1.18]; p = 0.15). Conclusion: In conclusion, our findings indicate CD163+ can provide prognostic utility in OSCC. However, our data suggests CD68+ TAMs were not associated with any prognostic relevance in OSCC patients, whereas PD-L1 expression may prove to be a differential prognostic marker dependent on tumour location and stage of progression.

Chohan MH ，Perry M ，Laurance-Young P ，Salih VM ，Foey AD ... -  《-》

Prognostic significance of CD68(+) and CD163(+) tumor associated macrophages in head and neck squamous cell carcinoma: A systematic review and meta-analysis.

Tumor associated macrophages (TAMs) are among the most abundant cells of the tumor microenvironment. Several studies have been performed to investigate whether TAM markers, namely CD68 and CD163, could serve as prognostic factors in patients with squamous cell carcinoma of the head and neck (SCCHN). The aim of this systematic review and meta-analysis was to synthetize the available evidence of the literature about the role of CD68+ and CD163+ TAMs as prognostic factors in SCCHN. This systematic review was performed according to the guidelines reported in the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Meta-analysis of overall survival, disease-free survival and progression-free survival was performed using the inverse of variance test. A random- or a fixed- effect model was used on the basis of the presence of heterogeneity. Risk of bias assessment and subgroup analysis were also performed. High stromal expression of CD163+ TAMs correlated with both poor overall survival (HR, 2.26; 95% CI: [1.47, 3.47]; P < 0.001) and progression-free survival (HR, 2.29; 95% CI: [1.11, 4.71]; P = 0.03). Conversely, abundance of CD68+ TAMs was not associated with overall survival (HR, 1.25; 95% CI: [0.86, 1.80]; P = 0.24) and disease-free survival (HR, 2.06; 95% CI: [0.84, 5.05]; P = 0.11). Findings from this study revealed that whilst IHC analysis of the generic macrophage marker CD68+ has no prognostic utility in patients with SCCHN, the M2-like marker CD163+ predicts poor prognosis. Our data suggest that assessment of CD163+ TAMs in SCCHN has potential for future clinical use. Further well-standardized studies should be performed to confirm these results.

Troiano G ，Caponio VCA ，Adipietro I ，Tepedino M ，Santoro R ，Laino L ，Lo Russo L ，Cirillo N ，Lo Muzio L ... -  《-》

CD163(+)CD204(+) tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma.

Kubota K ，Moriyama M ，Furukawa S ，Rafiul HASM ，Maruse Y ，Jinno T ，Tanaka A ，Ohta M ，Ishiguro N ，Yamauchi M ，Sakamoto M ，Maehara T ，Hayashida JN ，Kawano S ，Kiyoshima T ，Nakamura S ... -  《Scientific Reports》

Macrophages in Oral Carcinomas: Relationship with Cancer Stem Cell Markers and PD-L1 Expression.

Suárez-Sánchez FJ ，Lequerica-Fernández P ，Suárez-Canto J ，Rodrigo JP ，Rodriguez-Santamarta T ，Domínguez-Iglesias F ，García-Pedrero JM ，de Vicente JC ... -  《Cancers》

The prognostic role of tumor associated macrophages in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis.

Head and neck squamous cell carcinoma (HNSCC) is an immunogenic cancer type, and tumor associated macrophages (TAMs) are a major component of the tumor microenvironment (TME). In this systematic review and meta-analysis, studies assessing tumor infiltration with CD68+, iNOS+, HLA-DR+, CD11b+, CD163+, CD206+, and CD204+TAMs were included, and correlation to survival hazard was studied. A low number of CD68+TAMs correlated to better overall survival (OS) in multivariate analysis (HR 1.36 95 %CI (1.07-1.72) P = .01). CD68+TAMs did not correlate to disease free survival (DFS), disease specific survival (DSS), progression free survival (PFS), or recurrence free survival (RFS). A low number of CD163+TAMs correlated to better OS in uni- and multivariate analysis (resp. HR 2.65 95 %CI (1.57-4.46) P = .01 and HR 2.42 95 %CI (1.72-3.41) P < .001). A low number of CD163+TAMs also correlated to better DFS and PFS, whereas a low number of CD204+TAMs only correlated to PFS. While IHC analysis of pan macrophage marker CD68 and M2-like marker CD163 both show prognostic utility in OS, CD163 is a stronger prognosticator, as indicated by multivariate meta-analysis. CD163+TAMs also correlate to DFS and PFS; outcomes that are more relevant to patients, thus showing promising results for future clinical implementation.

Bisheshar SK ，van der Kamp MF ，de Ruiter EJ ，Ruiter LN ，van der Vegt B ，Breimer GE ，Willems SM ... -  《-》