Recurrent immunogenic neoantigens and their cognate T-cell receptors in treatment-resistant metastatic prostate cancer.

IF 33.3 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-10-08 DOI:10.1158/2159-8290.cd-24-1213

Nofar Gumpert,Shira Sagie,Claudia Arnedo-Pac,Tomer Babu,Chen Weller,Abel Gonzalez-Perez,Yuan Wang,Lucas Michel Todó,Ronen Levy,Xi Chen,Polina Greenberg,Maria Dayan-Rubinov,Elizabeta Yakubovich,Talya Wasserman-Bartov,Mirie Zerbib,Jianhui Gong,Ryan J Rebernick,Anna Oliveira Tercero,Laura Agundez Muriel,Gil Benedek,Merav Kedmi,Roni Oren,Shifra Ben-Dor,Yishai Levin,Olga G Troyanskaya,Aslı D Munzur,Alexander W Wyatt,Marcin P Cieslik,David A Quigley,Eliezer M Van Allen,Niroshana Anandasabapathy,Joaquin Mateo,Xinbo Yang,Francisco Martínez-Jiménez,Nuria Lopez-Bigas,Yardena Samuels

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引用次数: 0

Abstract

New approaches that generate long-lasting therapeutic responses in therapy-resistant metastatic cancer patients are urgently needed. To address this challenge, we developed SpotNeoMet, a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neo-peptides presented by common HLAs. Using HLA-immunopeptidomics, we discovered three novel neopeptides derived from Androgen Receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCRs) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y specific TCRs are highly specific and kill prostate cancer cells presenting AR neo-peptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for mCRPC patients. Moreover, SpotNeoMet offers a systematic route to identify 'HLA-peptide' pairs and their cognate TCRs across treatment-resistant cancers.

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复发性免疫原性新抗原及其同源t细胞受体在治疗抵抗性转移性前列腺癌中的作用。

迫切需要在治疗耐药的转移性癌症患者中产生持久治疗反应的新方法。为了应对这一挑战，我们开发了SpotNeoMet，这是一种新的数据驱动管道，可以系统地识别治疗耐药患者中反复出现的新肽。我们确定了七个治疗耐药突变，预测产生由常见hla呈现的新肽。利用hla免疫多肽组学，我们发现了三个新的多肽来源于雄激素受体（AR） H875Y，这是一种常见的转移性去势抵抗性前列腺癌（mCRPC）突变。我们验证了这些新抗原具有高度免疫原性，然后从健康供体外周血单个核细胞中分离和表征同源t细胞受体（TCRs）。我们证明了AR H875Y特异性tcr具有高度特异性，并在体外和体内杀死呈现AR新肽的前列腺癌细胞。我们的新产品线为mCRPC患者确定了新的免疫治疗靶点和潜在的治疗方案。此外，SpotNeoMet提供了一种系统的途径来识别治疗耐药癌症中的“hla -肽”对及其同源tcr。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.