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NK-Dependent Increases in CCL22 Secretion Selectively Recruits Regulatory T Cells to the Tumor Microenvironment¹

Adam W. Mailloux^2,* and M. Rita I. Young^3,,,

^* Department of Microbiology and Immunology, Department of Otolaryngology, and Department of Medicine, Medical University of South Carolina, Charleston, SC 29403; and Research Service (151), Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 2940

Tumor-induced immune suppression involves the accumulation of immune-suppressive infiltrates in the microenvironment. This study demonstrates increased numbers of CD4⁺CD25⁺FoxP3⁺ regulatory T cells (Tregs) in the lungs of C57BL/6 mice bearing a metastatic Lewis lung carcinoma (LLC) variant. These Tregs suppressed the proliferation of endogenous CD4⁺CD25^– cells and expressed higher levels of the chemokine receptor CCR4 than other types of T cells. LLC-bearing lungs secreted elevated levels of the CCR4-associated chemokine CCL22 compared with normal lungs. However, CCL22 was not secreted by LLC or normal epithelial controls, suggesting that CCL22 is secreted by a nonepithelial component of the microenvironment. Migration assays revealed that medium conditioned by LLC-bearing lungs selectively recruited Tregs at higher frequencies than did medium conditioned by normal lungs. Neutralization of CCL22 significantly reduced this selective recruitment toward both conditioned media. A series of immunomagnetic isolations, FACS, and flow cytometric analyses were used to isolate different cellular fractions from both normal and LLC-bearing lungs. When isolated, only the NK-containing fractions secreted CCL22, and the same fraction isolated from LLC-bearing lungs secreted higher levels. Depletion of NK cells from both normal and LLC-bearing lung tissue significantly reduced CCL22 secretion, suggesting that a large portion of secreted CCL22 is NK cell dependent. Flow cytometric analysis of the lung NK compartments revealed no significant increase in NK cell numbers across LLC-bearing lung tissue as a whole as compared with normal tissue. However, immunofluorescent staining revealed an increased frequency of NK cells at the tumor periphery that were closely associated with the elevated FoxP3⁺ infiltrate.

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 This work was supported by the Medical Research Service of the Veteran’s Affairs and by National Institute of Health Grants MRIY CA97813 and CA8566.

² Current address: 114 Doughty Street, Strom Thurmond Building Room 547, Charleston, SC 29403. E-mail address: maillou{at}musc.edu

³ Address correspondence and reprint requests to Dr. M. Rita I. Young, Research Service, (151), 109 Bee Street, Ralph H. Johnson Veterans Affairs Hospital, Charleston, SC 29401-5799. E-mail adress: rita.young{at}med.va.gov

⁴ Abbreviations used in this paper: Treg, regulatory T cell; LLC, Lewis lung carcinoma; MFI, mean fluorescence intensity; ND, not detected.