Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.
Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.
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DOI：
10.1038/s41586-022-04735-9
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发表时间：
2022-06
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
癌症免疫编辑是癌症的一个标志，它预测淋巴细胞会杀死免疫原性较高的癌细胞，从而导致免疫原性较低的克隆在群体中占主导地位。尽管在小鼠身上得到了证实，但免疫编辑是否在人类癌症中自然发生仍不清楚。为了解决这个问题，我们研究了 70 种人类胰腺癌在 10 年间的演变过程。我们发现，尽管有更多的时间积累突变，但在原发肿瘤中具有较强 T 细胞活性的罕见胰腺癌长期幸存者会发展出遗传异质性较低的复发肿瘤，免疫原性突变（新抗原）较少。为了量化免疫编辑是否是这些观察结果的基础，我们通过两个特征推断新抗原具有免疫原性（高质量）：“非自体”基于新抗原与已知抗原的相似性，以及“自体”基于新抗原与野生型肽相比差异性结合 MHC 或激活 T 细胞所需的抗原距离。利用这些特征，我们将癌症克隆适应性估计为 T 细胞识别高质量新抗原的总成本，并被致癌突变的收益所抵消。通过这个模型，我们预测了肿瘤的克隆进化，以揭示胰腺癌的长期幸存者会发展出高质量新抗原较少的复发性肿瘤。因此，我们提交的证据表明人类免疫系统自然地编辑新抗原。此外，我们提出了一个模型来预测免疫压力如何诱导癌细胞群随着时间的推移而进化。更广泛地说，我们的结果表明，免疫系统从根本上监视宿主的基因变化以抑制癌症。人类免疫系统自然地编辑高质量新抗原的癌症。
Cancer immunoediting is a hallmark of cancer that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features—‘non-selfness’ based on neoantigen similarity to known antigens, and ‘selfness’ based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer. The human immune system naturally edits cancers of high-quality neoantigens.
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影响因子：
8.8
作者：
Ino Y;Yamazaki-Itoh R;Shimada K;Iwasaki M;Kosuge T;Kanai Y;Hiraoka N
通讯作者：
Hiraoka N
CD155/TIGIT轴可促进并保持表达新抗原的胰腺癌的免疫逃避。
影响因子：
50.3
作者：
Freed-Pastor WA;Lambert LJ;Ely ZA;Pattada NB;Bhutkar A;Eng G;Mercer KL;Garcia AP;Lin L;Rideout WM 3rd;Hwang WL;Schenkel JM;Jaeger AM;Bronson RT;Westcott PMK;Hether TD;Divakar P;Reeves JW;Deshpande V;Delorey T;Phillips D;Yilmaz OH;Regev A;Jacks T
通讯作者：
Jacks T
影响因子：
64.5
作者：
Jiménez-Sánchez A;Memon D;Pourpe S;Veeraraghavan H;Li Y;Vargas HA;Gill MB;Park KJ;Zivanovic O;Konner J;Ricca J;Zamarin D;Walther T;Aghajanian C;Wolchok JD;Sala E;Merghoub T;Snyder A;Miller ML
通讯作者：
Miller ML
影响因子：
64.5
作者：
Birnbaum ME;Mendoza JL;Sethi DK;Dong S;Glanville J;Dobbins J;Ozkan E;Davis MM;Wucherpfennig KW;Garcia KC
通讯作者：
Garcia KC
影响因子：
64.8
作者：
Matsushita, Hirokazu;Vesely, Matthew D.;Koboldt, Daniel C.;Rickert, Charles G.;Uppaluri, Ravindra;Magrini, Vincent J.;Arthur, Cora D.;White, J. Michael;Chen, Yee-Shiuan;Shea, Lauren K.;Hundal, Jasreet;Wendl, Michael C.;Demeter, Ryan;Wylie, Todd;Allison, James P.;Smyth, Mark J.;Old, Lloyd J.;Mardis, Elaine R.;Schreiber, Robert D.
通讯作者：
Schreiber, Robert D.