Harter Patrick N, Bernatz Simon, Scholz Alexander, Zeiner Pia S, Zinke Jenny, Kiyose Makoto, Blasel Stella, Beschorner Rudi, Senft Christian, Bender Benjamin, Ronellenfitsch Michael W, Wikman Harriet, Glatzel Markus, Meinhardt Matthias, Juratli Tareq A, Steinbach Joachim P, Plate Karl H, Wischhusen Jörg, Weide Benjamin, Mittelbronn Michel
Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.
German Cancer Consortium (DKTK), Heidelberg, Germany.
Oncotarget. 2015 Dec 1;6(38):40836-49. doi: 10.18632/oncotarget.5696.
The activation of immune cells by targeting checkpoint inhibitors showed promising results with increased patient survival in distinct primary cancers. Since only limited data exist for human brain metastases, we aimed at characterizing tumor infiltrating lymphocytes (TILs) and expression of immune checkpoints in the respective tumors. Two brain metastases cohorts, a mixed entity cohort (n = 252) and a breast carcinoma validation cohort (n = 96) were analyzed for CD3+, CD8+, FOXP3+, PD-1+ lymphocytes and PD-L1+ tumor cells by immunohistochemistry. Analyses for association with clinico-epidemiological and neuroradiological parameters such as patient survival or tumor size were performed. TILs infiltrated brain metastases in three different patterns (stromal, peritumoral, diffuse). While carcinomas often show a strong stromal infiltration, TILs in melanomas often diffusely infiltrate the tumors. Highest levels of CD3+ and CD8+ lymphocytes were seen in renal cell carcinomas (RCC) and strongest PD-1 levels on RCCs and melanomas. High amounts of TILs, high ratios of PD-1+/CD8+ cells and high levels of PD-L1 were negatively correlated with brain metastases size, indicating that in smaller brain metastases CD8+ immune response might get blocked. PD-L1 expression strongly correlated with TILs and FOXP3 expression. No significant association of patient survival with TILs was observed, while high levels of PD-L1 showed a strong trend towards better survival in melanoma brain metastases (Log-Rank p = 0.0537). In summary, melanomas and RCCs seem to be the most immunogenic entities. Differences in immunotherapeutic response between tumor entities regarding brain metastases might be attributable to this finding and need further investigation in larger patient cohorts.
通过靶向检查点抑制剂激活免疫细胞在不同的原发性癌症中显示出有希望的结果，患者生存率有所提高。由于关于人脑转移瘤的可用数据有限，我们旨在表征相应肿瘤中肿瘤浸润淋巴细胞（TILs）和免疫检查点的表达。通过免疫组织化学分析了两个脑转移瘤队列，一个混合实体队列（n = 252）和一个乳腺癌验证队列（n = 96）中的CD3 +、CD8 +、FOXP3 +、PD - 1 +淋巴细胞和PD - L1 +肿瘤细胞。进行了与临床流行病学和神经放射学参数（如患者生存率或肿瘤大小）相关性的分析。TILs以三种不同模式浸润脑转移瘤（基质、瘤周、弥漫性）。虽然癌通常表现出强烈的基质浸润，但黑色素瘤中的TILs通常弥漫性浸润肿瘤。肾细胞癌（RCC）中CD3 +和CD8 +淋巴细胞水平最高，RCC和黑色素瘤上的PD - 1水平最强。大量的TILs、高比例的PD - 1 + / CD8 +细胞和高水平的PD - L1与脑转移瘤大小呈负相关，表明在较小的脑转移瘤中CD8 +免疫反应可能被阻断。PD - L1表达与TILs和FOXP3表达密切相关。未观察到患者生存率与TILs有显著关联，而高水平的PD - L1在黑色素瘤脑转移瘤中显示出更好生存率的强烈趋势（对数秩检验p = 0.0537）。总之，黑色素瘤和RCC似乎是最具免疫原性的实体。关于脑转移瘤，不同肿瘤实体之间免疫治疗反应的差异可能归因于这一发现，需要在更大的患者队列中进一步研究。
