High infiltration of CD68+ macrophages is associated with poor prognoses of head and neck squamous cell carcinoma patients and is influenced by human papillomavirus
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Imelda Seminerio1, Nadège Kindt1, Géraldine Descamps1, Justine Bellier1,5, Jérôme R. Lechien1, Quentin Mat1, Charles Pottier2, Fabrice Journé1,3 and Sven Saussez1,4
1Department of Human Anatomy and Experimental Oncology, Research Institute for Health Sciences and Technology, Faculty of Medicine and Pharmacy, University of Mons, Mons B-7000, Belgium
2Department of Pathology, C.H.U., SART TILMAN, University of Liège, Liège 4000, Belgium
3Laboratory of Oncology and Experimental Surgery, Jules Bordet Institute, Université Libre de Bruxelles, Brussels 1000, Belgium
4Department of Oto-Rhino-Laryngology, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels B-1000, Belgium
5Present address: Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liège 4000, Belgium
Imelda Seminerio, email: firstname.lastname@example.org
Sven Saussez, email: email@example.com
Keywords: head and neck squamous cell carcinoma; human papillomavirus; CD68; macrophages; mouse
Received: November 30, 2017 Accepted: January 19, 2018 Published: January 24, 2018
Incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinomas (HNSCCs) has increased over the last few decades. The reaction of the host immune system to these tumors remains biologically complex. Here, we investigated CD68+ macrophage numbers, reporting the prognostic value in comparison to other risk factors. We also examined CD68+ macrophage infiltration during disease progression regarding the impact of HPV infection, and we studied the role of HPV16-E6/E7 oncoproteins in CD68+ macrophage recruitment. CD68+ macrophage numbers were evaluated in 10 cases of tumor-free peri-tumoral epithelia, 43 cases of low-grade dysplasia, 45 cases of high-grade dysplasia and 110 cases of carcinoma. Our in vivo model was developed in 80 C3H/HeN mice orthotopically injected with HPV16-E6, -E7 or -E6/E7-transfected SCC-VII cell lines. High CD68+ macrophage numbers in the intra-tumoral compartment were associated with shorter patient survival (recurrence-free survival: p = 0.001; overall survival: p = 0.01). Multivariate analyses reported that CD68+ macrophage infiltration and tumor stage were strong and independent prognostic factors of HNSCC. CD68+ macrophage numbers increased during HNSCC progression both in intra-epithelial (p < 0.001) and stromal compartments (p < 0.001). A higher density of CD68+ macrophages was observed in advanced stages (p = 0.004). Patients with transcriptionally active HPV infections had higher CD68+ macrophage density than did HPV-negative patients (p = 0.003). CD68+ macrophage infiltration was higher in HPV-E7+ and −E6/E7+ mouse tumors than in -E6+ tumors (p = 0.029 and p < 0.001). In conclusion, the extent of CD68+ macrophage infiltration is a significant prognostic factor for HNSCC patients. The recruitment of macrophages increases during disease progression and is influenced by the HPV virus.
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