Tumor-infiltrating lymphocytes and tumor-associated macrophages as potential predictors of lymph node metastases in major salivary gland cancers

Abstract

PurposeThe purpose of this study is to define if tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) could represent potential predictors of lymph node metastases (LNM) in salivary gland cancers (SGC).MethodsA selected number of immunohistochemical markers related to TILs (CD3, CD4, CD68, and FOXP3) and TAMs (CD68 and CD163) were investigated on major salivary gland cancers. TIL and TAM densities were measured on digital images using the open-source QuPath both in the tumor interior (TI) and invasive margin (IM). Correlation with pathologic N classification and follow-up clinical data was investigated.ResultsA total of 25 consecutive patients (men: 11; median age: 62.0) were included. Densities of CD3+ IM (OR = 7.7, 95% CI 1.2–51.2), CD8+ TI (OR = 7.7, 95% CI 1.2–51.2), CD8+ IM (OR = 7.7, 95% CI 1.2–51.2), FOXP3+ TI (OR = 24.0, 95% CI 2.2–255.9), CD68+ TI (OR = 7.7, 95% CI 1.2–51.2), and CD163+ IM (OR = 7.7, 95% CI 1.2 – 51.2), and the Immunoscore CD8/CD3 (OR = 1.9, 95% CI 1.1–3.4) were significantly associated with LNM (p < 0.05). CD3+ TI density was significantly associated with tumor recurrence and death (HR = 5.8, 95% CI 1.5–22.6; p < 0.05).ConclusionA high density of specific TIL and TAM subpopulations might be correlated with a higher probability of LNM in SGC.

CD3 and CD20 Expressions and Infiltrating Patterns in Salivary Gland Tumors

“…In addition, the low expression of CD3 in the intra-tumoral area of malignant SGTs showed a significant association with those still alive patients. In line with our findings, another investigation revealed that the only low-grade MEC with no recurrences during the follow-up showed low CD3 positivity [20]. Elevated CD3 expression may not necessarily reflect T cell functionality.…”

“…AdCCs demonstrated low CD3 and scant CD20 expression in the intra-tumoural areas and lower TIL counts compared to those for MECs and PAs in peripheral areas. This tumor is considered to be low in immunogenic levels (poor immunogenicity) [16,20]. In line with our data, some authors have observed that most AdCC cases present with few infiltrating immune cells, including T lymphocytes [18].…”

“…Kesar et al indicated that MECs have an indifferent SGT in immune infiltration [19]. However, a recent finding reported by Virgilio et al remarked that MECs have high CD3 and CD8 infiltrates in both internal and invasive tumoral margins, which could represent potential predictors of lymph node metastases [20]. The present study also showed a high immune infiltrate expression, especially CD3, in both intra-tumoral and peripheral regions, but they are diffuse in the center and scattered at the periphery.…”

“…Data regarding microenvironment immune response in SGTs are limited and, until recently, only four studies have implicated the intensity of TIL response in different malignant SGTs [15,16,19,20]. To address this point speculatively, the spatial immune pattern (TIL) and intensity expression of SGTs (including two malignant and one benign lesion) were analyzed based on their correlations with clinicopathologic parameters.…”

“…This can be represented by low or high levels of immune phenotypes [15]. Recently, Virgilio et al classified MEC as a high levels of immune phenotypes, expressing high levels of CD3 and CD8 infiltrates in the tumoral interior and invasive margin; this was associated with local or distant recurrences [20]. Meanwhile, Kang et al found a downregulation in the immune-related genes [21].…”