Research Papers:

Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens

Marina K Baine, Gabriela Turcu, Christopher R Zito, Adebowale J Adeniran, Robert L Camp, Lieping Chen, Harriet M. Kluger _ and Lucia B Jilaveanu

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Oncotarget. 2015; 6:24990-25002. https://doi.org/10.18632/oncotarget.4572

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Marina K. Baine1, Gabriela Turcu2, Christopher R. Zito1,3, Adebowale J. Adeniran4, Robert L. Camp4, Lieping Chen5, Harriet M. Kluger1,*, Lucia B. Jilaveanu1,*

1Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

2Department of Dermatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

3Department of Biology, School of Health and Natural Sciences, University of Saint Joseph, West Hartford, CT, USA

4Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

5Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

*These authors have contributed equally to this work

Correspondence to:

Harriet M. Kluger, e-mail: [email protected]

Keywords: tumor infiltrating lymphocytes (TILs), renal cell carcinoma (RCC), primary, metastatic

Received: May 05, 2015     Accepted: June 29, 2015     Published: July 10, 2015


Renal cell carcinoma (RCC) is one of the most chemo- and radio-resistant malignancies, with poor associated patient survival if the disease metastasizes. With recent advances in immunotherapy, particularly with PD-1/PD-L1 blockade, outcomes are improving, but a substantial subset of patients does not respond to the new agents. Identifying such patients and improving the therapeutic ratio has been a challenge, although much effort has been made to study PD-1/PD-L1 status in pre-treatment tumor. However, tumor infiltrating lymphocyte (TIL) content might also be predictive of response, and our goal was to characterize TIL content and PD-L1 expression in RCC tumors from various anatomic sites. Utilizing a quantitative immunofluorescence technique, TIL subsets were examined in matched primary and metastatic specimens. In metastatic specimens, we found an association between low CD8+ to Foxp3+ T-cell ratios and high levels of PD-L1. High PD-L1-expressing metastases were also found to be associated with tumors that were high in both CD4+ and Foxp3+ T-cell content. Taken together these results provide the basis for combining agents that target the PD-1/PD-L1 pathway with agonist of immune activation, particularly in treating RCC metastases with unfavorable tumor characteristics and microenvironment. In addition, CD8+ TIL density and CD8:Foxp3 T-cell ratio were higher in primary than metastatic specimens, supporting the need to assess distant sites for predictive biomarkers when treating disseminated disease.

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