Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens.
Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens.
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DOI：
10.18632/oncotarget.4572
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Jilaveanu LB
中科院分区：
文献类型：
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作者：
Baine MK;Turcu G;Zito CR;Adeniran AJ;Camp RL;Chen L;Kluger HM;Jilaveanu LB
肾细胞癌（RCC）是最具化疗和放射抗性的恶性肿瘤之一，如果疾病转移，患者生存率很低。随着免疫疗法的最新进展，特别是PD-1/PD-L1阻断，结果正在改善，但相当一部分患者对新药没有反应。识别这些患者并提高治疗率一直是一个挑战，尽管已经做出了很多努力来研究治疗前肿瘤中的PD-1/PD-L1状态。然而，肿瘤浸润淋巴细胞（TIL）含量也可能是反应的预测，我们的目标是表征不同解剖部位RCC肿瘤中的TIL含量和PD-L1表达。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查TIL亚群。在转移性标本中，我们发现低CD8 +/Foxp3 + T细胞比率与高水平PD-L1之间存在相关性。还发现高PD-L1表达转移与CD4+和Foxp3 + T细胞含量高的肿瘤相关。总之，这些结果为靶向PD-1/PD-L1通路的药物与免疫活化激动剂的联合用药提供了基础，特别是在治疗具有不利肿瘤特征和微环境的RCC转移瘤方面。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，支持在治疗播散性疾病时评估远端部位的预测性生物标志物的必要性。
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.