Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases.
Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases.
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DOI：
10.18632/oncotarget.5696
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发表时间：
2015-12-01
期刊：
影响因子：
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通讯作者：
Mittelbronn M
中科院分区：
文献类型：
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作者：
Harter PN;Bernatz S;Scholz A;Zeiner PS;Zinke J;Kiyose M;Blasel S;Beschorner R;Senft C;Bender B;Ronellenfitsch MW;Wikman H;Glatzel M;Meinhardt M;Juratli TA;Steinbach JP;Plate KH;Wischhusen J;Weide B;Mittelbronn M
通过靶向检查点抑制剂激活免疫细胞显示出有希望的结果，在不同的原发性癌症中增加了患者的存活率。由于人脑转移瘤的数据有限，我们的目的是表征肿瘤浸润淋巴细胞（TIL）和相应肿瘤中免疫检查点的表达。通过免疫组织化学分析了两个脑转移队列，一个混合实体队列（n = 252）和一个乳腺癌验证队列（n = 96）的CD 3+、CD 8+、FOXP 3+、PD-1+淋巴细胞和PD-L1+肿瘤细胞。分析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的关联。TIL以三种不同的模式（基质、瘤周、弥漫）浸润脑转移瘤。虽然癌通常显示出强烈的间质浸润，但黑色素瘤中的TIL通常弥漫性浸润肿瘤。肾细胞癌（RCC）中CD 3+和CD 8+淋巴细胞水平最高，而RCC和黑色素瘤中PD-1水平最强。高数量的TIL、高比例的PD-1+/CD 8+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，CD 8+免疫应答可能被阻断。PD-L1表达与TIL和FOXP 3表达密切相关。未观察到患者生存期与TIL的显著相关性，而高水平的PD-L1显示出黑色素瘤脑转移瘤患者生存期更好的强烈趋势（Log-Rank p = 0.0537）。总之，黑色素瘤和RCC似乎是最具免疫原性的实体。肿瘤实体之间关于脑转移的免疫应答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。
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.