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. 2013 Jun 1;6(3):282-9.
doi: 10.1593/tlo.13256. Print 2013 Jun.

Tumor-infiltrating PD1-Positive Lymphocytes and FoxP3-Positive Regulatory T Cells Predict Distant Metastatic Relapse and Survival of Clear Cell Renal Cell Carcinoma

Myoung Jae Kang  1 , Kyoung Min Kim, Jun Sang Bae, Ho Sung Park, Ho Lee, Myoung Ja Chung, Woo Sung Moon, Dong Geun Lee, Kyu Yun Jang
Affiliations

Tumor-infiltrating PD1-Positive Lymphocytes and FoxP3-Positive Regulatory T Cells Predict Distant Metastatic Relapse and Survival of Clear Cell Renal Cell Carcinoma

Myoung Jae Kang et al. Transl Oncol. .

Abstract

Background: Clear cell renal cell carcinoma (CRCC) is the most common malignant tumor of the kidney, and the clinical outcome of CRCC is related with the metastatic potential of CRCC. A significant proportion of metastatic CRCC remains incurable. Recently, immunotherapy against specific targets such as programmed death 1 (PD1) has been adapted for fatal cases of CRCC.

Materials and methods: In this study, we aimed to evaluate the potential of tumor-infiltrating PD1-positive lymphocytes or FoxP3-positive regulatory T cells (Tregs) as predictors of the metastatic potential or prognosis of CRCC and investigate possible correlations with Epstein-Barr virus (EBV) infection in 199 cases of CRCC.

Results: PD1 positivity, high Treg number, and EBV infection all predicted poor overall survival (OS) by univariate analysis. PD1 positivity and high Treg numbers were also significantly correlated with more distant metastatic relapse (DMR) and poor relapse-free survival (RFS) by univariate analysis. PD1 positivity and high Treg number were independent prognostic indicators for OS. In addition, PD1 positivity was an independent predictor of RFS and DMR. EBV infection was an independent predictor of OS of CRCC.

Conclusion: This study demonstrates that intratumoral infiltration of PD1-positive or FoxP3-positive lymphocytes can be used as significant prognostic indicators of CRCC and PD1 positivity could be very helpful in the prediction of latent distant metastasis of CRCCs. Therefore, evaluation of the infiltration of PD-positive cells or Tregs in CRCC may be useful diagnostic tools for the selection of patients who could benefit from PD1- or Treg-based immunotherapy.

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Figures

Figure 1
Figure 1
Immunohistochemical staining for FoxP3 and PD1 and in situ hybridization for EBER in CRCC. (A and B) PD1-positive cells (arrowheads) in the CRCC. (C and D) Cases with low numbers of FoxP3-positive Tregs (C) and high numbers of FoxP3-positive Tregs (D). Arrows indicate FoxP3-positive Tregs. (E) A positive signal for EBER appears in the nuclei (empty arrowheads) and cytoplasm of tumor cells. (F) Tumor-infiltrating inflammatory cells also stain positive for EBER. The representative field area of one microscopic image for PD1 and FoxP3 immunostaining is 0.086 mm2. Original magnification, x400.
Figure 2
Figure 2
Kaplan-Meier survival analysis of RCC. (A–F) OS and RFS according to TNM stage (A), nuclear grade of tumor cells (B), histologic tumor necrosis (C), intratumoral infiltration of PD1-positive cells (D) and FoxP3-positive Tregs (E), and EBV infection (F) in CRCC patients.
Figure 3
Figure 3
Kaplan-Meier analysis according to the combined intratumoral infiltration patterns of PD1-positive lymphocytes and FoxP3-positive Tregs in CRCC. (A–C) DMR, RFS, and OS in overall CRCC (A), stage I CRCC (B), and high stage (stages II–IV) CRCC (C).
See this image and copyright information in PMC

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