ATRT-34. TARGETING PRIMARY CILIOGENESIS IN ATYPICAL TERATOID/RHABDOID TUMORS
ATRT-34. TARGETING PRIMARY CILIOGENESIS IN ATYPICAL TERATOID/RHABDOID TUMORS
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ATRT-34 靶向非典型畸胎瘤/横纹肌样肿瘤的原发纤毛发生
DOI：
10.1093/neuonc/noy059.031
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发表时间：
2018
期刊：
影响因子：
15.9
通讯作者：
Remke M
中科院分区：
文献类型：
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作者：
Blümel L;Kerl K;Berlandi J;Thiel K;Tegeder I;Jeibmann A;Picard D;Langini M;Stühler K;Meyer F;Malzkorn B;Liebau MC;Johann PD;Erkek S;Kool K;Pfister SM;Frühwald MC;Borkhardt A;Reifenberger G;Hasselblatt M;Remke M
为了评估AT/RT的免疫浸润，我们进行了联合免疫组化，多参数流式细胞术和一系列的49人AT/RT的转录组学分析。这揭示了大量的异质性，与AT/RT的一些亚组显示出突出的免疫浸润。详细地说，我们的分析表明：i）骨髓细胞是最丰富的免疫群体，包括小胶质细胞和非驻留的促肿瘤M2极化巨噬细胞，ii）肿瘤浸润淋巴细胞由相等比例的CD 4+和CD 8 + T细胞组成，几乎没有调节性T细胞，iii）免疫调节分子PD-L1和TIM-3以高水平表达。CD 8 + T细胞的肿瘤内细胞溶解活性与干扰素γ和α特征高度相关，证实了适应性和先天性免疫细胞参与抗肿瘤应答。我们实验室最近建立的AT/RT基因工程小鼠模型概括了许多这些特征，包括淋巴细胞和骨髓细胞共享相似的表型特征的重要浸润。使用该模型，我们发现阻断PD-1/PD-L1通路显著损害肿瘤生长并诱导对第二次植入的记忆，证实了抗肿瘤T细胞记忆应答。与TIM-3阻断剂组合显示出协同作用。此外，通过用poly（I：C）激活TLR 3靶向骨髓浸润诱导了有效的抗肿瘤作用，其与PD-1阻断相结合，导致超过85%的治疗小鼠的肿瘤完全消退。总之，我们证明了免疫浸润是AT/RT的一种复发特性，免疫治疗，特别是联合治疗方案，具有很好的治疗潜力。
In order to evaluate the immune infiltrate of AT/RT, we conducted a combined immunohistochemical, multiparametric flow cytometry and transcriptomic analysis of a series of 49 human AT/RT. This revealed substantial heterogeneity, with some subgroups of AT/RT showing a prominent immune infiltrate. In details, our analyses indicated that: i) myeloid cells were the most abundant immune population, including both microglial cells and non-resident pro-tumoral M2-polarized macrophages, ii) tumor-infiltrating lymphocytes consisted in equal proportions of CD4+ and CD8+ T cells with few regulatory T cells, and iii) immune modulatory molecules PD-L1 and TIM-3 were expressed at high levels. Intratumoral cytolytic activity of CD8+ T cells highly correlated with both interferon gamma and alpha signatures, confirming the involvement of both adaptive and innate immune cells in the anti-tumor response. A genetically engineered mouse model of AT/RT recently established in our laboratory recapitulates many of these traits, including important infiltration by both lymphoid and myeloid cells sharing similar phenotypic characteristics. Using this model, we showed that blockade of the PD-1/PD-L1 pathway significantly impaired tumor growth and induced memory against a second engraftment, confirming an anti-tumoral T cell memory response. Combination with TIM-3 blockade showed synergistic effects. Additionally, targeting the myeloid infiltrate by TLR3 activation with poly(I:C) induced a potent anti-tumor effect which, combined with PD-1 blockade, led to complete tumor regression in over 85% of treated mice. In conclusion, we demonstrate that immune infiltration is a recurrent property of AT/RT and that immunotherapy, particularly combination regimens, have promising therapeutic potential.