Clinical Significance of CD163+ and CD68+ Tumor-associated Macrophages in High-risk HPV-related Cervical Cancer

Abstract

Objective. To explore the influence of M2-polarized tumor-associated macrophages (TAMs) on high-risk human papillomavirus (hr-HPV)-related cervical carcinogenesis and metastasis.Methods. CD68+ and CD163+ macrophages were examined immunohistochemically in a series of 130 samples, including 26 cases of normal cervical tissues, 59 cases of cervical intraepithelial neoplasia (CIN), and 45 cases of squamous cell carcinoma (SCC), and the results were statistically analyzed. The macrophage count was corrected for the epithelial and stromal compartments respectively. Clinical data were also obtained.Results. High counts of CD68+ and CD163+ macrophages were associated with hr-HPV infection (both p < 0.05) and positively correlated with cervical carcinogenesis (Spearman's rho = 0.478, p = 0.000; Spearman's rho = 0.676, p =0.000, respectively). The immunostaining pattern of CD163 exhibited clearer background than that of CD68. CD163+ macrophages showed a more obviously increasing migration into the epithelium along with the progression of CIN to invasive cancer. Notably, a high index of CD163+ macrophages was significantly associated with higher FIGO stages (p = 0.009) and lymph node metastasis (p = 0.012), but a similar finding was not found for CD68+ macrophages (p = 0.067, p = 0.079, respectively).Conclusions. Our study supported a critical role of TAMs as a prospective predictor for hr-HPV-related cervical carcinogenesis. CD163, as a promising TAMs marker, is superior to CD68 for predicting the malignant transformation and metastatic potential of cervical cancer.

The role of the hypoxia‐Nrp‐1 axis in the activation of M2‐like tumor‐associated macrophages in the tumor microenvironment of cervical cancer

“…Immunohistochemistry (IHC) was performed as previously described . Briefly, consecutive 4‐µm paraffin sections were deparaffinized and rehydrated.…”

“…Immunohistochemistry (IHC) was performed as previously described. 26 Briefly, consecutive 4-µm paraffin sections were deparaffinized and rehydrated. Endogenous peroxidase activity was blocked by incubation for 30 min with 3% H 2 O 2 in methanol at room temperature (RT).…”

The role of the innate and adaptive immune response in HPV‐associated oropharyngeal squamous cell carcinoma

“…These effects result in promotion of carcinogenesis and metastasis. Although not specific to HPV‐associated OPSCC, TAMs are linked to poor prognosis, progression of disease, locoregional metastasis, and higher grade lesions . The M1 phenotype, however, is associated with tumor regression and inducing HPV clearance by favoring a TH1 response .…”

Activities of stromal and immune cells in HPV-related cancers

“…It was reported that poor prognosis is linked to increased levels of CD163 (TAM marker with M2 phenotype), CSF-1 (colony-stimulating factor-1), major regulator of macrophage lineage, and Arginase-1 (Arg-1) – markers of TAM’s activity – in several cancers including the HPV-related ones [ 12 , 25 , 28 ]. Increased infiltration of CD163 macrophages in stromal and peri-tumoral areas were associated with malignancy progression, lymph node metastasis, higher FIGO stages [ 29 ], higher lesion grades and cervical cancer specimens [ 28 , 30 ].…”