Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets.
Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets.
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DOI：
10.1172/jci125301
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发表时间：
2019-05
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影响因子：
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通讯作者：
A. Monette;A. Morou;N. Al-Banna;L. Rousseau;J. Lattouf;Sara Rahmati;T. Tokár;J. Routy;J. Cailhier;D. Kaufmann;I. Jurisica;R. Lapointe
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作者：
A. Monette;A. Morou;N. Al-Banna;L. Rousseau;J. Lattouf;Sara Rahmati;T. Tokár;J. Routy;J. Cailhier;D. Kaufmann;I. Jurisica;R. Lapointe
基本原理肿瘤浸润淋巴细胞与积极结果广泛相关，但携带着针对未解决的癌症的全身免疫反应失败的关键指标。癌症免疫疗法可以逆转其耐受表型，同时保留与循环免疫细胞共享的肿瘤反应性和新抗原特异性。目的 我们进行了全面的转录组分析，以确定透明细胞肾细胞癌中循环淋巴细胞和肿瘤浸润淋巴细胞常见的基因特征。与疾病结果相关的调节基因也在其他癌症类型中得到了验证。研究结果 利用生物信息学，我们确定了免疫反应失败的实用诊断标志物和可操作的目标。在循环淋巴细胞上，LEF1、FASLG 和 MMP9 三个基因可以有效地将患者与健康对照供体进行分层。从它们与癌症免疫疗法和微生物感染耐药性的关系中，我们不仅发现了泛癌症，而且发现了泛病理学失败的免疫反应谱。一个突出的淋巴细胞基质金属肽酶细胞迁移途径是一系列疾病和肿瘤免疫原性的核心，与多种癌症复发相关，并确定了一种可行的、非侵入性的泛病理诊断方法。结论 我们确定的非侵入性差异表达基因值得未来研究，以开发其在精准诊断和精准泛疾病免疫治疗中的潜力。
Rationale Tumor infiltrating lymphocytes are widely associated with positive outcomes, yet carry key indicators of a systemic failed immune response against unresolved cancer. Cancer immunotherapies can reverse their tolerance phenotypes, while preserving tumor-reactivity and neoantigen-specificity shared with circulating immune cells. Objectives We performed comprehensive transcriptomic analyses to identify gene signatures common to circulating and tumor infiltrating lymphocytes in the context of clear cell renal cell carcinoma. Modulated genes also associated with disease outcome were validated in other cancer types. Findings Using bioinformatics, we identified practical diagnostic markers and actionable targets of the failed immune response. On circulating lymphocytes, three genes, LEF1, FASLG, and MMP9, could efficiently stratify patients from healthy control donors. From their associations with resistance to cancer immunotherapies and microbial infections, we uncovered not only pan-cancer, but pan-pathology failed immune response profiles. A prominent lymphocytic matrix metallopeptidase cell migration pathway, is central to a panoply of diseases and tumor immunogenicity, correlates with multi-cancer recurrence, and identifies a feasible, non-invasive approach to pan-pathology diagnoses. Conclusions The non-invasive differently expressed genes we have identified warrant future investigation towards the development of their potential in precision diagnostics and precision pan-disease immunotherapeutics.