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科学家揭示黑色素瘤抗肿瘤免疫的新机制
2020-12-17 14:02

荷兰癌症研究所Reuven Agami和以色列魏茨曼科学研究所Yardena Samuels团队合作的一项最新研究表明,在黑色素瘤中抗肿瘤免疫诱导了异常肽的产生。2020年12月16日出版的《自然》杂志在线发表了这项成果。

在本研究中,研究人员在黑素瘤细胞中利用核糖体分析探究了长时间干扰素-γ(IFNγ)处理对mRNA翻译的影响。值得注意的是,研究人员观察到核糖体在色氨酸密码子下游积累以及如预期所想的在色氨酸密码子处停滞。这表明核糖体在不存在色氨酸的情况下绕过了色氨酸密码子。对这些与色氨酸相关核糖体堆积物(研究人员将其称为“ W凸点”)的详细检查表明,它们的特征在于核糖体移码事件。与之一致的是,报告基因检测与蛋白质组学和免疫肽组学分析相结合,证明了核糖体移码的发生以及IFNγ处理后细胞表面异常反式构架肽的产生和呈递。用异常肽来刺激健康供体的原始T细胞会引发异常肽特异性T细胞的产生。

总之,该结果表明,IFNγ诱导的IDO1介导的色氨酸耗竭通过促进肽段组学多样化而在黑素瘤细胞的免疫识别中发挥作用。

据悉,大量浸润性T细胞的产生和强IFNγ信号反映了广泛的肿瘤炎症,这改善了黑素瘤患者对检查点免疫治疗的反应。但是,许多肿瘤通过激活免疫抑制途径而逃逸。已知的逃逸机制是吲哚胺2,3-二加氧酶1(IDO1)通过犬尿氨酸途径产生色氨酸代谢物,这是由IFNγ诱导的。然而,与单独PD1途径阻滞相比,在黑色素瘤患者中使用IDO1抑制结合PD1阻滞的临床试验并未改善治疗效果,这表明对IDO1的作用及其随后的降解以及色氨酸在mRNA翻译和癌症进展中的作用亟待阐明。

附:英文原文

Title: Anti-tumour immunity induces aberrant peptide presentation in melanoma

Author: Osnat Bartok, Abhijeet Pataskar, Remco Nagel, Maarja Laos, Eden Goldfarb, Deborah Hayoun, Ronen Levy, Pierre-Rene Krner, Inger Z. M. Kreuger, Julien Champagne, Esther A. Zaal, Onno B. Bleijerveld, Xinyao Huang, Juliana Kenski, Jennifer Wargo, Alexander Brandis, Yishai Levin, Orel Mizrahi, Michal Alon, Sacha Lebon, Weiwen Yang, Morten M. Nielsen, Noam Stern-Ginossar, Maarten Altelaar, Celia R. Berkers, Tamar Geiger, Daniel S. Peeper, Johanna Olweus, Yardena Samuels, Reuven Agami

Issue&Volume: 2020-12-16

Abstract: Extensive tumour inflammation, which is reflected by high levels of infiltrating T cells and interferon-γ (IFNγ) signalling, improves the response of patients with melanoma to checkpoint immunotherapy1,2. Many tumours, however, escape by activating cellular pathways that lead to immunosuppression. One such mechanism is the production of tryptophan metabolites along the kynurenine pathway by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which is induced by IFNγ3,4,5. However, clinical trials using inhibition of IDO1 in combination with blockade of the PD1 pathway in patients with melanoma did not improve the efficacy of treatment compared to PD1 pathway blockade alone6,7, pointing to an incomplete understanding of the role of IDO1 and the consequent degradation of tryptophan in mRNA translation and cancer progression. Here we used ribosome profiling in melanoma cells to investigate the effects of prolonged IFNγ treatment on mRNA translation. Notably, we observed accumulations of ribosomes downstream of tryptophan codons, along with their expected stalling at the tryptophan codon. This suggested that ribosomes bypass tryptophan codons in the absence of tryptophan. A detailed examination of these tryptophan-associated accumulations of ribosomes—which we term ‘W-bumps’—showed that they were characterized by ribosomal frameshifting events. Consistently, reporter assays combined with proteomic and immunopeptidomic analyses demonstrated the induction of ribosomal frameshifting, and the generation and presentation of aberrant trans-frame peptides at the cell surface after treatment with IFNγ. Priming of naive T cells from healthy donors with aberrant peptides induced peptide-specific T cells. Together, our results suggest that IDO1-mediated depletion of tryptophan, which is induced by IFNγ, has a role in the immune recognition of melanoma cells by contributing to diversification of the peptidome landscape.

DOI: 10.1038/s41586-020-03054-1

Source: https://www.nature.com/articles/s41586-020-03054-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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