Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy

Yung Che Chen; Chang Chun Hsiao; Kuang Den Chen; Yu Chiang Hung; Ching Yuan Wu; Chien Hao Lie; Shih Feng Liu; Ming Tse Sung; Chung Jen Chen; Ting Ya Wang; Jen Chieh Chang; Petrus Tang; Wen Feng Fang; Yi Hsi Wang; Yu Hsiu Chung; Tung Ying Chao; Sum Yee Leung; Mao Chang Su; Chin Chou Wang; Meng Chih Lin

doi:10.1371/journal.pone.0057053

Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy

Yung Che Chen, Chang Chun Hsiao, Kuang Den Chen, Yu Chiang Hung, Ching Yuan Wu, Chien Hao Lie, Shih Feng Liu, Ming Tse Sung, Chung Jen Chen, Ting Ya Wang, Jen Chieh Chang, Petrus Tang, Wen Feng Fang, Yi Hsi Wang, Yu Hsiu Chung, Tung Ying Chao, Sum Yee Leung, Mao Chang Su, Chin Chou Wang, Meng Chih Lin^*

^*Corresponding author for this work

Chang Gung University

Research output: Contribution to journal › Journal Article › peer-review

21 Scopus citations

Abstract

Introduction: Increasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy. Methods: To test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment. Results: Sixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p = 0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p = 0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p = 0.01) was the only independent factor associated with three-year overall mortality. Conclusions: Our results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC.

Original language	English
Article number	e57053
Journal	PLoS ONE
Volume	8
Issue number	2
DOIs	https://doi.org/10.1371/journal.pone.0057053
State	Published - 25 02 2013

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Chen, Y. C., Hsiao, C. C., Chen, K. D., Hung, Y. C., Wu, C. Y., Lie, C. H., Liu, S. F., Sung, M. T., Chen, C. J., Wang, T. Y., Chang, J. C., Tang, P., Fang, W. F., Wang, Y. H., Chung, Y. H., Chao, T. Y., Leung, S. Y., Su, M. C., Wang, C. C., & Lin, M. C. (2013). Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy. PLoS ONE, 8(2), Article e57053. https://doi.org/10.1371/journal.pone.0057053

@article{8713180141a542c29ec1f43035aa1955,

title = "Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy",

abstract = "Introduction: Increasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy. Methods: To test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment. Results: Sixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p = 0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p = 0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p = 0.01) was the only independent factor associated with three-year overall mortality. Conclusions: Our results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC.",

author = "Chen, {Yung Che} and Hsiao, {Chang Chun} and Chen, {Kuang Den} and Hung, {Yu Chiang} and Wu, {Ching Yuan} and Lie, {Chien Hao} and Liu, {Shih Feng} and Sung, {Ming Tse} and Chen, {Chung Jen} and Wang, {Ting Ya} and Chang, {Jen Chieh} and Petrus Tang and Fang, {Wen Feng} and Wang, {Yi Hsi} and Chung, {Yu Hsiu} and Chao, {Tung Ying} and Leung, {Sum Yee} and Su, {Mao Chang} and Wang, {Chin Chou} and Lin, {Meng Chih}",

year = "2013",

month = feb,

day = "25",

doi = "10.1371/journal.pone.0057053",

language = "英语",

volume = "8",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "2",

}

Chen, YC, Hsiao, CC, Chen, KD, Hung, YC, Wu, CY, Lie, CH, Liu, SF, Sung, MT, Chen, CJ, Wang, TY, Chang, JC, Tang, P, Fang, WF, Wang, YH, Chung, YH, Chao, TY, Leung, SY, Su, MC, Wang, CC & Lin, MC 2013, 'Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy', PLoS ONE, vol. 8, no. 2, e57053. https://doi.org/10.1371/journal.pone.0057053

TY - JOUR

T1 - Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy

AU - Chen, Yung Che

AU - Hsiao, Chang Chun

AU - Chen, Kuang Den

AU - Hung, Yu Chiang

AU - Wu, Ching Yuan

AU - Lie, Chien Hao

AU - Liu, Shih Feng

AU - Sung, Ming Tse

AU - Chen, Chung Jen

AU - Wang, Ting Ya

AU - Chang, Jen Chieh

AU - Tang, Petrus

AU - Fang, Wen Feng

AU - Wang, Yi Hsi

AU - Chung, Yu Hsiu

AU - Chao, Tung Ying

AU - Leung, Sum Yee

AU - Su, Mao Chang

AU - Wang, Chin Chou

AU - Lin, Meng Chih

PY - 2013/2/25

Y1 - 2013/2/25

N2 - Introduction: Increasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy. Methods: To test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment. Results: Sixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p = 0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p = 0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p = 0.01) was the only independent factor associated with three-year overall mortality. Conclusions: Our results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC.

AB - Introduction: Increasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy. Methods: To test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment. Results: Sixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p = 0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p = 0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p = 0.01) was the only independent factor associated with three-year overall mortality. Conclusions: Our results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC.

UR - http://www.scopus.com/inward/record.url?scp=84874522854&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0057053

DO - 10.1371/journal.pone.0057053

M3 - 文章

C2 - 23451142

AN - SCOPUS:84874522854

SN - 1932-6203

VL - 8

JO - PLoS ONE

JF - PLoS ONE

IS - 2

M1 - e57053

ER -

Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy

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