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CD4⁺CXCR4^highCD69⁺ T Cells Accumulate in Lung Adenocarcinoma

Ori Wald^1,*, Uzi Izhar^1,*,, Gail Amir, Shani Avniel^*, Yochai Bar-Shavit^*, Hanna Wald^*, Ido D. Weiss^*, Eithan Galun^* and Amnon Peled^2,*

^* Goldyne Savad Institute of Gene Therapy, Department of Pathology, and Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel

The chemokine receptor CXCR4 is involved in the growth and metastasis of tumor cells. However, the expression of its ligand, the chemokine CXCL12, in tumors and its role in regulating the accumulation of immune cells within the tumors is not clear. Using ELISA and immunohistochemistry we found that CXCL12 is expressed in the majority of nonsmall cell lung cancer tissue sections obtained from stage IA to IIB nonsmall cell lung cancer patients undergoing operation. Histopathologic examination of these sections indicated that high CXCL12 expression correlated with increased tumor inflammation. In addition, disease recurrence rates in a subgroup of adenocarcinoma patients showed a tendency to correlate with high CXCL12 expression in the tumor. Isolation of adenocarcinoma-infiltrating immune cells demonstrated an increase in the percentage of CD4⁺CD69⁺CXCR4⁺ T cells as compared with normal lung tissue. About 30% of these cells expressed the regulatory T cell markers CD25^high and FoxP3. The percentage of CD8 T cells within the tumor did not change, however; the percentage of NK and NK T cells was significantly reduced. In correlation with CXCR4 expression, CD4 T cells showed increased migration in response to CXCL12 compared with CD8 T cells and NK cells. Overall, these observations suggest that CXCL12 expression may influence tumor progression by shaping the immune cell population infiltrating lung adenocarcinoma tumors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ O.W. and U.I. contributed equally to this work.

² Address correspondence and reprint requests to Dr. Amnon Peled, Hadassah University Hospital, Gene Therapy Institute, P.O. Box 12000, Jerusalem, Israel. E-mail address: peled{at}hadassah.org.il

³ Abbreviations used in this paper: NSCLC, nonsmall cell lung cancer; HIF, hypoxia-inducible factor; PTC, papillary thyroid carcinoma.

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