Immune activation status of CD8+ T cells infiltrating non-small cell lung cancer

doi:10.1016/j.lungcan.2003.11.004

Lung Cancer

Volume 44, Issue 2, May 2004, Pages 143-147

https://doi.org/10.1016/j.lungcan.2003.11.004 Get rights and content

Abstract

In a variety of human cancers, the presence of tumor-infiltrating T lymphocytes (TILs) is associated with tumor regression and favorable prognosis. Local interferon (IFN)-γ secretion from activated T cells is supposed to induce a specific immune response leading to tumor-specific cytotoxicity. Nonetheless, significance and properties of TILs still remains controversial in lung cancer patients. We determined CD8+ T cell counts in 31 patients with non-small cell lung cancer (NSCLC) by immunohistochemistry, and assessed T-cell immune activation status in a subset of patients by measuring IFN-γ mRNA expression by quantitative PCR (TaqMan). Semi-quantitative immunohistochemical analysis revealed significantly higher CD8+ T cell counts within the tumor as when compared to the invasive margin. CD8+ T cells immune activation status, represented in the IFN-γ/CD8 mRNA ratio, correlated with the median number of CD8+ T cells presented at the tumor-host interface. Neither tumor histology and grade, nor CD8+ T cell counts and IFN-γ/CD8 ratio could demonstrate an influence on overall survival in these patients. Our results indicate that CD8+ T cells infiltrating the tumor cell nests may be inadequately activated and thus incapable of mounting an effective anti-tumor immune response.

Introduction

In a variety of human cancers, including small cell lung cancer (SCLC), the presence of tumor-infiltrating T lymphocytes (TILs) is associated with tumor regression and favorable prognosis [1], [2], [3]. TILs participate in tumor growth control through T cell cytotoxicity and the release of different soluble mediators. Interferon-γ (IFN-γ) is an important regulator of the immune response, whose significance in tumor immunity has recently been demonstrated in a model of receptor knockout mice [4]. In humans, local IFN-γ secretion from activated CD8+ T cells is associated with their in vivo efficacy [5], [6], [7] and has been explored extensively in a variety of clinical settings [8], [9], [10]. Although reports indicate that lung cancer cells can be recognized by autologous cytotoxic T cells (CTLs) and might, therefore, be susceptible to specific immunotherapy [11], [12], the significance of TILs in lung cancer remains controversial [13], [14], [15]. Given the fact that patients with NSCLC exhibit high recurrence rates and poor long-term survival, novel tools are of need to identify those patients who may respond to adjunctive therapies, such as immunotherapy. We assessed CD8+ T cell counts in patients with NSCLC as well as their activation status by IFN-γ quantitative PCR [16], [17]. Our results indicate that in human NSCLC, peritumoral (PT) CD8+ T cells exhibit higher expression of IFN-γ message, a finding indicative of sustained T-cell reactivity, when compared to lymphocytes within the tumor cell nests.

Section snippets

Tumor specimens

A total of 31 lung cancer samples were collected following surgical resection, after obtaining prior informed consent of the patient. Tumor samples were used for further analysis only, if microscopy confirmed representative tissue, which was then used for both cell-counting methodology and molecular analysis (as outlined below).

Immunohistochemistry and cell counting

Formalin-fixed paraffin-embedded material was stained with anti-human CD8 mouse monoclonal antibody (DakoCytomation, Glostrup, Denmark) using alkaline

CD8+ T cell counts in non-small cell lung cancer

Tumor histology, tumor grade, and semi-quantitative grading of intratumoral (IT^∗) and peritumoral (PT^∗) CD8+ T cells for all patients as well as their clinical stage is summarized in Table 1. Evaluated tumors were frequently infiltrated and/or surrounded by CD8+ T-cells. Median T cell counts revealed that 11 (35%) of the investigated cases demonstrated absent to moderate intratumoral infiltrate. Heavy IT infiltration was present in 20 (65%) of cases, respectively. Absent to scant peritumoral

Discussion

The presence of tumor-infiltrating lymphocytes is often considered as a favorable prognostic parameter [1], [2], [11], [21]. Although circulating CD8+ cytotoxic T cells may exhibit in vitro reactivity against tumor antigens [17], in lung cancer the role of TILs and their prognostic significance is discussed controversial. In order to overcome tumor, effector mechnisms of infiltrating CD8+ T lymphocytes (e.g. expression of Fas-ligand, release of perforin/granzymes and IFN-γ), also more likely to

Acknowledgements

A.T. and R.G. work was supported by Kanton Zürich Cancer League. We thank Beatrix Müller for technical assistance.

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Immune activation status of CD8+ T cells infiltrating non-small cell lung cancer

Abstract

Introduction

Section snippets

Tumor specimens

Immunohistochemistry and cell counting

CD8+ T cell counts in non-small cell lung cancer

Discussion

Acknowledgements

Clin. Immunol.

J. Immunol. Methods

Lung Cancer

Lung Cancer

Blood

Am. J. Pathol.

Trends Immunol.

Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas

Cancer Res.

Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer

N. Engl. J. Med.

A high number of tumor-infiltrating lymphocytes are associated with a small tumor size, low tumor stage, and a favorable prognosis in operated small cell lung carcinoma

Clin. Cancer Res.

IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity

Nature

Interferon gamma and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes

J. Exp. Med.

Local secretion of IFN-gamma induces an antitumor response: comparison between T cells plus IL-2 and IFN-gamma transfected tumor cells

J. Immunother.

Functional analysis of antigen-specific T lymphocytes by serial measurement of gene expression in peripheral blood mononuclear cells and tumor specimens

J. Immunol.

Status of activation of circulating vaccine-elicited CD8+ T cells

J. Immunol.