Distinct T cell functions enable efficient immunoediting and prevent tumor emergence of developing sarcomas

IF 44.5 1区 医学 Q1 CELL BIOLOGY
Julie F. Cheung, Brian G. Hunt, Shudipto Wahed, Elaine Cheng, Kelli A. Connolly, Srividhya Venkatesan, Jennifer L. Loza, Ishan Bansal, Eric Fagerberg, Emily A. Kessler, Clémence Riffard, Jessica Buck, John Attanasio, Emily R. Borr, Wei Wei, Ivana William, Brittany Fitzgerald, Nikhil S. Joshi
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Abstract

T cells edit tumors by eliminating neoantigen-expressing tumor cells. Yet, how and when this is achieved remains uncertain. Using a murine sarcoma model with fluorescent neoantigens, we found that tumors developed later and in fewer T cell-sufficient mice (∼53% penetrance) than T cell-deficient mice (∼100%). With T cells, all emergent tumor cells had silenced neoantigens, but neoantigen-negative tumor cells were also present in every T cell-deficient mouse. This suggested silencing was necessary but not sufficient for outgrowth. Genetic removal of neoantigens restored tumor penetrance if implemented on day 5 post-tumor initiation, but not day 10, because CD8+ and CD4+ T cells infiltrated the tissue and eliminated most neoantigen-positive and -negative tumor cells within 8 days. Single-cell analyses on day-7 tumors showed oncogenic changes including increased proliferation and T cell-dependent upregulation of the IFNγ-response gene Cd274 (PD-L1). T cell-depletion rescued both neoantigen-positive and -negative cells, while IFNγ blockade rescued only negative cells. This shows that T cells efficiently edit sarcomas of neoantigens and prevent early tumors via IFNγ-independent and IFNγ-dependent (bystander) mechanisms.

Abstract Image

不同的T细胞功能能够有效地进行免疫编辑,并防止肿瘤出现发展中的肉瘤
T细胞通过消除表达新抗原的肿瘤细胞来编辑肿瘤。然而,如何以及何时实现这一目标仍不确定。使用带有荧光新抗原的小鼠肉瘤模型,我们发现肿瘤在T细胞充足的小鼠(约53%外显率)中比T细胞缺陷小鼠(约100%)发展得更晚,并且在更少的小鼠中(约53%外显率)。在T细胞中,所有新生肿瘤细胞都有沉默的新抗原,但在每个T细胞缺陷小鼠中也存在新抗原阴性的肿瘤细胞。这表明沉默是必要的,但不足以促进生长。如果在肿瘤发生后第5天进行遗传去除新抗原,则恢复肿瘤外显率,而不是第10天,因为CD8+和CD4+ T细胞浸润组织并在8天内消除了大多数新抗原阳性和阴性的肿瘤细胞。第7天的单细胞分析显示肿瘤发生了致癌变化,包括增殖增加和T细胞依赖的ifn γ反应基因Cd274 (PD-L1)上调。T细胞耗竭可以拯救新抗原阳性和阴性细胞,而IFNγ阻断只能拯救阴性细胞。这表明T细胞通过ifn γ-不依赖和ifn γ-依赖(旁观者)机制有效地编辑新抗原肉瘤并预防早期肿瘤。
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来源期刊
Cancer Cell
Cancer Cell 医学-肿瘤学
CiteScore
55.20
自引率
1.20%
发文量
179
审稿时长
4-8 weeks
期刊介绍: Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.
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