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Phenotypic Analysis of Prostate-Infiltrating Lymphocytes Reveals T_H17 and T_reg Skewing

Authors' Affiliations: ¹ Department of Urology, James Buchanan Brady Urological Institute, ² Oncology and ³ Pathology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Charles G. Drake, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, CRB 452, Baltimore, MD 21231. Phone: 410-502-7523; Fax: 410-614-0549; E-mail: drakech{at}jhmi.edu.

Purpose: Pathologic examination of prostate glands removed from patients with prostate cancer commonly reveals infiltrating CD4⁺ and CD8⁺ T cells. Little is known about the phenotype of these cells, despite accumulating evidence suggesting a potential role for chronic inflammation in the etiology of prostate cancer.

Experimental Design: We developed a technique that samples the majority of the peripheral prostate through serial needle aspirates. CD4⁺ prostate-infiltrating lymphocytes (PIL) were isolated using magnetic beads and analyzed for subset skewing using both flow cytometry and quantitative reverse transcription-PCR. The transcriptional profile of fluorescence-activated cell sorted prostate-infiltrating regulatory T cells (CD4⁺, CD25⁺, GITR⁺) was compared with naïve, peripheral blood T cells using microarray analysis.

Results: CD4⁺ PIL showed a paucity of T_H2 (interleukin-4–secreting) cells, a surprising finding given the generally accepted association of these cells with chronic, smoldering inflammation. Instead, CD4⁺ PIL seemed to be skewed towards a regulatory T_reg phenotype (FoxP3⁺) as well as towards the T_H17 phenotype (interleukin-17⁺). We also found that a preponderance of T_H17-mediated inflammation was associated with a lower pathologic Gleason score. These protein level data were reflected at the message level, as analyzed by quantitative reverse transcription-PCR. Microarray analysis of pooled prostate-infiltrating T_reg revealed expected T_reg-associated transcripts (FoxP3, CTLA-4, GITR, LAG-3) as well as a number of unique cell surface markers that may serve as additional T_reg markers.

Conclusion: Taken together, these data suggest that T_H17 and/or T_reg CD4⁺ T cells (rather than T_H2 T cells) may be involved in the development or progression of prostate cancer.