Tumor Infiltrating CD8+ and Foxp3+ Lymphocytes Correlate to Clinical Outcome and Human Papillomavirus (HPV) Status in Tonsillar Cancer

Abstract

BackgroundHuman papillomavirus (HPV) is a causative factor for tonsillar squamous cell carcinoma (TSCC) and patients with HPV positive (HPV+) TSCC have a better clinical outcome than those with HPV negative (HPV−) TSCC. However, since not all patients with HPV+TSCC respond to treatment, additional biomarkers are needed together with HPV status to better predict response to therapy and to individualize treatment. For this purpose, we examined whether the number of tumor infiltrating cytotoxic and regulatory T-cells in TSCC correlated to HPV status and to clinical outcome.MethodsFormalin fixed paraffin embedded TSCC, previously analysed for HPV DNA, derived from 83 patients, were divided into four groups depending on the HPV status of the tumor and clinical outcome. Tumors were stained by immunohistochemistry and evaluated for the number of infiltrating cytotoxic (CD8+) and regulatory (Foxp3+) T-cells.ResultsA high CD8+ T-cell infiltration was significantly positively correlated to a good clinical outcome in both patients with HPV+ and HPV- TSCC patients. Similarly, a high CD8+/Foxp3+ TIL ratio was correlated to a 3-year disease free survival. Furthermore, HPV+TSCC had in comparison to HPV−TSCC, higher numbers of infiltrating CD8+ and Foxp3+ T-cells.ConclusionsIn conclusion, a positive correlation between a high number of infiltrating CD8+ cells and clinical outcome indicates that CD8+ cells may contribute to a beneficial clinical outcome in TSCC patients, and may potentially serve as a biomarker. Likewise, the CD8+/Foxp3+cell ratio can potentially be used for the same purpose.

Human papilloma virus status of penile squamous cell carcinoma is associated with differences in tumour-infiltrating T lymphocytes

“…In SCC of the head and neck, where like in penile SCC carcinogenesis might be HPV-associated or HPV-independent, data about tumour-infiltrating lymphocytes are conflicting. While no difference in the number of T cells in SCC of the head and neck was seen in one study [24], other studies reported a positive correlation between HPV status and the number of CD3 [25], CD8alpha [26] or CD8 [27] expressing T lymphocytes.…”

The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications

“…Several studies have demonstrated an increased population of CD8+ lymphocytes, Tregs and increased CD8+/Treg ratio in HPV+ OPC, which are associated with improved prognosis (31,32).…”

Erratum: Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer

“…Only few studies have examined the prognostic impact of TIL expression in correlation with the HPV status in HNSCC patients. Nasman et al (2012) found that high CD8 expression was correlated to a good clinical outcome in both HPV-positive-and HPV-negative patients. Similar findings were reported from Nordfors et al (2013), and the authors hypothesised that the increased expression of CD8 þ TILs could contribute to the better response of HPV-positive patients to therapy.…”

“…One study demonstrated an increased T-cell response against the E7 oncoprotein epitope in the blood of HPV-positive patients, whereas another work revealed an increased T-cell proliferation in response to HPV E6 and E7 oncoproteins (Bontkes et al, 2000). Some studies have shown that strong CD8 expression is associated with better prognosis in HPV-positive patients (Nasman et al, 2012;Nordfors et al, 2013) but others have failed to reproduce this finding (Kong et al, 2009;Wansom et al, 2012) Although previous reports have examined the role of TILs in HNSCC, the majority of the studies were characterised by small sample size and/or use of heterogeneous treatment schedules (Ginos et al, 2004;Le et al, 2005;Badoual et al, 2006). In the present work, we aimed to investigate the potential biologic importance of TILs in patients with HNSCC treated with primary CRT.…”