title: Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens.
abstract: 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.
authors: Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors: Marina K
authors: MK
authors: Baine
authors: Department of Dermatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
authors: Gabriela
authors: G
authors: Turcu
authors: Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.|Department of Biology, School of Health and Natural Sciences, University of Saint Joseph, West Hartford, CT, USA.
authors: Christopher R
authors: CR
authors: Zito
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: Adebowale J
authors: AJ
authors: Adeniran
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: Robert L
authors: RL
authors: Camp
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors: Lieping
authors: L
authors: Chen
authors: Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors: Harriet M
authors: HM
authors: Kluger
authors: Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors: Lucia B
authors: LB
authors: Jilaveanu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D060890:B7-H1 Antigen / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors
keywords: metastatic; primary; renal cell carcinoma (RCC); tumor infiltrating lymphocytes (TILs)