The effect of lung cancer on cytokine expression in peripheral blood mononuclear cells.

Barbara G Heerdt,Ankur A Patel,Sai Yendamuri,Robert J Korst,David H Chang,John R Rutledge,Leonard H Augenlicht

doi:10.1371/journal.pone.0064456

Abstract

The purpose of this study is to evaluate cytokine expression by peripheral blood mononuclear cells (PBMC) from stage I lung cancer patients and to confirm these expression patterns by exposing PBMCs to lung cancer cells in vitro. Five altered cytokines in stage I lung cancer patients (CCL3, IL8, IL1β, CXCL10, sIL2Rα) were identified in plasma from subjects (n = 15) before and after resection using a 30-plex panel protein assay. Gene expression studies using quantitative RT-qPCR were performed on PBMCs from stage I lung cancer patients (n = 62) before and after resection, and compared to non-cancer patients (n = 32) before and after surgery for benign disease. Co-culture experiments that exposed healthy donor PBMCs to lung cancer cells in vitro were performed to evaluate the effect on PBMC cytokine expression. PBMC gene expression of CCL3, IL8 and IL1β was higher in lung cancer patients compared to the same patients at each of four sequential timepoints after removal of their tumors, while CXCL10 and IL2Rα were essentially unchanged. This pattern was also detected when lung cancer patients were compared to non-cancer patients. When non-cancer patients underwent surgery for benign diseases, these cytokine expression changes were not demonstrable. Lung cancer cell lines, but not benign bronchial epithelial cells, induced similar changes in cytokine gene and protein expression by healthy donor PBMCs in an in vitro co-culture system. We conclude that PBMCs from stage I lung cancer patients possess distinct cytokine expression patterns compared to both non-cancer patients, and lung cancer patients following tumor removal. These expression patterns are replicated by healthy donor PBMCs exposed to lung cancer cell lines, but not benign bronchial epithelial cells in vitro. These findings have implications for understanding the immune response to lung cancer.

Highlights

Lung cancer remains the leading cause of cancer-related mortality in the United States, and is expected to account for more deaths in 2012 than colorectal, breast, and prostate cancers combined [1]
Identification of 5 genes for Further Investigation To corroborate the initial findings for the 21 targets identified by the Luminex assay, and to help define targets for further investigation, we interrogated a microarray database previously generated in our laboratory that compares patterns of gene expression in peripheral blood mononuclear cells (PBMC) obtained from stage I lung cancer patients before and after curative resection
The two cytokines which were found at the lowest levels prior to stage I lung cancer resection (CXCL10 and soluble IL2Ra) were both corroborated by the PBMC gene expression data from the microarray database

Summary

Introduction

Lung cancer remains the leading cause of cancer-related mortality in the United States, and is expected to account for more deaths in 2012 than colorectal, breast, and prostate cancers combined [1]. Lung cancer has been considered to be a poorly immunogenic malignancy, several lines of evidence suggest an influence of the host’s immune system in altering lung cancer development and progression These include reports of enhanced survival in lung cancer patients with postoperative infections [2], increased recurrence rates among patients who receive perioperative blood transfusions [3,4], and higher incidence rates among immunosuppressed individuals such as those who test positive for the Human Immunodeficiency Virus (HIV) [5]. Despite these observations, the role of the host immune system in the development and progression of lung cancer remains unclear. Cytokine and chemokine networks can be ‘‘hijacked’’ by cancer cells to provide an environment conducive to tumor growth [6,7]

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