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

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Abstract

Background

Human 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.

Methods

Formalin 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.

Results

A 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.

Conclusions

In 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.

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Most cited references 25

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Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer.

Paul Salama, Michael Phillips, Fabienne Grieu … (2009)

To determine the prognostic significance of FOXP3(+) lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8(+) and CD45RO(+) lymphocyte densities. Tissue microarrays and immunohistochemistry were used to assess the densities of CD8(+), CD45RO(+), and FOXP3(+) lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. FOXP3(+) Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8(+) and CD45RO(+) cell densities were lower. FOXP3(+) Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3(+) Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8(+) and CD45RO(+). High FOXP3(+) Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3(+) Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). FOXP3(+) Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8(+) and CD45RO(+) lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3(+) Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3(+) Treg density may help to improve the prognostication of early-stage colorectal cancer.

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Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers.

Cécile Badoual, Stéphane Hans, José Rodríguez … (2006)

CD4(+) T cells play a central role in initiating and maintaining anticancer immune responses. However, regulatory CD4(+)CD25(+) T cells which express Foxp3 have also been shown to inhibit antitumor effector T cells. In view of these heterogeneous CD4(+) T-cell populations, this study was designed to determine the prognostic value of various tumor-infiltrating CD4(+) T-cell populations in head and neck squamous cell carcinoma. Eighty-four newly diagnosed untreated patients with histologically proven primary head and neck squamous cell carcinoma were included in this study. Double or triple immunofluorescence staining was done to assess and quantify the activated CD4(+)CD69(+) T cells, regulatory CD4(+)Foxp3(+) T cells, and mixed CD4(+)CD25(+) T cells comprising both activated and regulatory T cells. On univariate analysis, high levels of tumor-infiltrating CD4(+)CD69(+) T cells were correlated with both better locoregional control (P = 0.01) and longer survival (P = 0.01). Infiltration by regulatory Foxp3(+)CD4(+) T cells was positively associated with a better locoregional control of the tumor. Multivariate analysis showed that the only significant prognostic factors related to locoregional control were T stage (P = 0.02) and CD4(+)Foxp3(+) T-cell infiltration of the tumor (P = 0.02). In the Cox multivariate analysis, only two variables influenced overall survival probability: T stage (P = 0.036) and CD4(+)CD69(+) T-cell infiltration (P = 0.017). This study shows that tumor-infiltrating activated CD4(+)CD69(+) T cells are associated with a good prognosis in head and neck squamous cell carcinoma. In addition, regulatory Foxp3(+)CD4(+) T cells are positively correlated with locoregional control may be through down-regulation of harmful inflammatory reaction, which could favor tumor progression.

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Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?

Anders Näsman, Per Attner, Lalle Hammarstedt … (2009)

In the county of Stockholm, between 1970 and 2002, we have previously reported a 3-fold parallel increase in the incidence of tonsillar squamous cell carcinoma (SCC) and the proportion of human papillomavirus (HPV) positive tonsillar SCC. Here, we have followed the above parameters in all patients (n = 120) diagnosed with tonsillar SCC during 2003-2007 in the same area, and also in correlation to our previous data. Ninety-eight pretreatment biopsies were available and presence of HPV DNA and HPV-16 E6 and E7 RNA were tested by polymerase chain reaction (PCR) and RT-PCR. Incidence data were obtained from the Swedish Cancer Registry. Data reported from 1970 to 2002 were also obtained for comparison. HPV DNA was present in 83 of 98 (85%) of the tonsillar SCC biopsies from 2003 to 2007 and 77 of these were HPV-16 positive. HPV-16 E6 and E7 RNA were found in 98% of 52 analyzed HPV-16 positive cases. The proportion of HPV-positive cancers had significantly increased both from 1970 to 2007 (p < 0.0001) as well from 2000 to 2007 (p < 0.01), with 68% (95% confidence interval (CI), 53-81) 2000-2002; 77% (95% CI, 63-87) 2003-2005; and 93% (95% CI, 82-99) 2006-2007. The incidence rate of HPV-positive tumors almost doubled each decade between 1970 and 2007, in parallel with a decline of HPV-negative tumors. In conclusion, the incidence of HPV-positive cancers is still increasing in the County of Stockholm, suggesting an epidemic of a virus-induced carcinoma, with soon practically all tonsillar SCC being HPV positive, as in cervical cancer. Copyright 2009 UICC.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 12 June 2012

Volume: 7

Issue: 6

Electronic Location Identifier: e38711

Affiliations

[1 ]Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

[2 ]Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

John Hopkins Medical School, United States of America

Author notes

* E-mail: torbjorn.ramqvist@ 123456ki.se

Conceived and designed the experiments: AN TR TD EMW. Performed the experiments: AR MR CN NG. Analyzed the data: AN HJ TR LH LM. Contributed reagents/materials/analysis tools: LH LM EMW. Wrote the paper: AN TD TR.

Article

Publisher ID: PONE-D-12-03982

DOI: 10.1371/journal.pone.0038711

PMC ID: 3373553

PubMed ID: 22701698

SO-VID: 1f6c7275-e912-478e-8a5f-1059d9562a21

Copyright © Näsman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 7 February 2012

Date accepted : 11 May 2012

Page count

Pages: 8

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