Baine Marina K, Turcu Gabriela, Zito Christopher R, Adeniran Adebowale J, Camp Robert L, Chen Lieping, Kluger Harriet M, Jilaveanu Lucia B
Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
Department of Dermatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
Oncotarget. 2015 Sep 22;6(28):24990-5002. doi: 10.18632/oncotarget.4572.
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.
肾细胞癌（RCC）是最具化疗和放疗抗性的恶性肿瘤之一，如果疾病发生转移，患者的生存预后较差。随着免疫疗法的最新进展，尤其是PD-1/PD-L1阻断疗法，治疗结果正在改善，但仍有相当一部分患者对这些新药物无反应。尽管在研究治疗前肿瘤中的PD-1/PD-L1状态方面已付出诸多努力，但识别此类患者并提高治疗率仍是一项挑战。然而，肿瘤浸润淋巴细胞（TIL）含量也可能预测反应，我们的目标是对来自不同解剖部位的RCC肿瘤中的TIL含量和PD-L1表达进行表征。利用定量免疫荧光技术，在匹配的原发性和转移性标本中检测TIL亚群。在转移性标本中，我们发现低CD8 +与Foxp3 + T细胞比率与高水平的PD-L1之间存在关联。还发现高表达PD-L1的转移灶与CD4 +和Foxp3 + T细胞含量均高的肿瘤有关。综合这些结果为将靶向PD-1/PD-L1途径的药物与免疫激活激动剂联合使用提供了依据，特别是在治疗具有不利肿瘤特征和微环境的RCC转移灶时。此外，原发性标本中的CD8 + TIL密度和CD8:Foxp3 T细胞比率高于转移性标本，这支持了在治疗播散性疾病时评估远处部位以寻找预测性生物标志物的必要性。
