研究揭示黑色素瘤免疫逃逸机制

本期文章：《免疫》：Online/在线发表

德国波恩大学Michael Hlzel课题组近日取得一项新成果。他们发现针对不同基因产物的过继性T细胞疗法，揭示了黑色素瘤的多种和背景相关免疫逃逸。2020年8月3日出版的《免疫》杂志发表了这项成果。

他们检查了提供CD8 + T细胞抗肿瘤免疫目标表位的基因产物调节和功能，如何影响治疗功效和耐药性。他们在同源黑色素瘤模型中，使用了基于CRISPR-Cas9的方法（CRISPitope），将相同模型的CD8 + T细胞表位融合到不同内源基因产物的C末端。通过相同表位特异性CD8 + T细胞的过继细胞转移（ACT），靶向黑素体蛋白或致癌CDK4R24C（细胞周期蛋白依赖性激酶4），揭示了多种遗传和非遗传免疫逃逸机制。

ACT针对黑素体蛋白，但不针对CDK4R24C，可促进黑素瘤去分化并增加髓样细胞浸润。CDK4R24C抗原的持久性与高干扰素和富含T细胞的肿瘤微环境有关，从而可以作为免疫疗法来抑制免疫检查点。因此，靶抗原的选择决定了复发性黑色素瘤的表型和免疫状况，这与癌症免疫疗法的设计有关。

研究人员表示，肿瘤免疫逃逸限制了对T细胞疗法的持久反应。

附：英文原文

Title: Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in Melanoma

Author: Maike Effern, Nicole Glodde, Matthias Braun, Jana Liebing, Helena N. Boll, Michelle Yong, Emma Bawden, Daniel Hinze, Debby van den Boorn-Konijnenberg, Mila Daoud, Pia Aymans, Jennifer Landsberg, Mark J. Smyth, Lukas Flatz, Thomas Tüting, Tobias Bald, Thomas Gebhardt, Michael Hlzel

Issue&Volume: 2020-08-03

Abstract: Tumor immune escape limits durable responses to T cell therapy. Here, we examinedhow regulation and function of gene products that provide the target epitopes forCD8+ T cell anti-tumor immunity influence therapeutic efficacy and resistance. We useda CRISPR-Cas9-based method (CRISPitope) in syngeneic melanoma models to fuse the samemodel CD8+ T cell epitope to the C-termini of different endogenous gene products. Targetingmelanosomal proteins or oncogenic CDK4R24C (Cyclin-dependent kinase 4) by adoptive cell transfer (ACT) of the same epitope-specificCD8+ T cells revealed diverse genetic and non-genetic immune escape mechanisms. ACT directedagainst melanosomal proteins, but not CDK4R24C, promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4R24C antigen persistence was associated with an interferon-high and T-cell-rich tumormicroenvironment, allowing for immune checkpoint inhibition as salvage therapy. Thus,the choice of target antigen determines the phenotype and immune contexture of recurrentmelanomas, with implications to the design of cancer immunotherapies.

DOI: 10.1016/j.immuni.2020.07.007

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30314-9

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