Genetics Department, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Department of Biomedical and Molecular Sciences and Obstetrics and Gynecology, Queen's University, K7L3N6, Kingston, Ontario, Canada.
J Immunother Cancer. 2019 Jun 7;7(1):148. doi: 10.1186/s40425-019-0619-8.
Molecular subtyping of urothelial cancer (UC) has significantly advanced the understanding of bladder tumor heterogeneity and development of prognostic and predictive biomarkers. Evolving evidence across cancers strongly suggests that tumor immunoediting has a profound impact on the behaviour of cancer cells and their adaptation to the co-evolving microenvironment and response to treatment. In alignment with these concepts, recent immune checkpoint blockade (ICB) therapies in UC have demonstrated the predictive potential of mutations in the DNA damage repair (DDR) genes. A comprehensive understanding of DDR gene inactivation associated expression of immune regulatory genes could thus aid in expansion of current immunotherapies and predictive biomarkers for the design of patient-tailored combination treatments.
We investigated pre-treatment tumor transcriptomic profiles of the five recently described molecular subtypes of muscle invasive urothelial cancer (MIUC; n = 408) from The Cancer Genome Atlas, to determine subtype specific immune cell abundance, expression of 67 immune regulatory genes, and association with DDR gene inactivation (via mutation, copy number alteration) profiles.
Analysis using CIBERSORT immune cell abundance determination tool showed significant differences in immune cell profiles and abundance between MIUC subtypes. Expression patterns of a selected panel of 67 genes including both immune stimulatory and inhibitory genes, showed significant associations with subtypes, and DDR gene mutation status.
Findings from our study provide compelling evidence for co-expression of multiple immune checkpoint genes including, PD-1, PD-L1, IDO1, TIGIT, TIM-3, TGFB1, LAG3, and others, that potentially contribute to compensatory immune evasion in bladder tumors. Our findings also emphasize the urgent need for biomarker discovery approaches that combine molecular subtype, DDR gene mutation status, tumor immune landscape classification, and immune checkpoint gene expression to increase the number of patients responding to immunotherapies.
尿路上皮癌（UC）的分子亚型已极大地促进了对膀胱肿瘤异质性和预后及预测生物标志物的发展的理解。癌症领域不断发展的证据强烈表明，肿瘤免疫编辑对癌细胞的行为及其对共进化的微环境的适应和对治疗的反应具有深远影响。与这些概念一致，最近 UC 中的免疫检查点阻断（ICB）疗法已经证明了 DNA 损伤修复（DDR）基因突变的预测潜力。因此，全面了解与 DDR 基因失活相关的免疫调节基因表达，有助于扩大当前的免疫疗法和预测生物标志物，以设计针对患者的联合治疗。
我们从癌症基因组图谱（TCGA）中研究了最近描述的 5 种肌肉浸润性尿路上皮癌（MIUC；n=408）的分子亚型的肿瘤转录组学特征，以确定亚型特异性免疫细胞丰度、67 个免疫调节基因的表达，并与 DDR 基因失活（通过突变、拷贝数改变）图谱相关联。
使用 CIBERSORT 免疫细胞丰度确定工具的分析表明，MIUC 亚型之间的免疫细胞谱和丰度存在显著差异。包括免疫刺激和抑制基因在内的 67 个基因的选定基因表达模式与亚型和 DDR 基因突变状态显著相关。
我们的研究结果为多个免疫检查点基因（包括 PD-1、PD-L1、IDO1、TIGIT、TIM-3、TGFB1、LAG3 等）的共表达提供了令人信服的证据，这些基因可能有助于膀胱肿瘤中的代偿性免疫逃逸。我们的研究结果还强调了迫切需要发现能够将分子亚型、DDR 基因突变状态、肿瘤免疫景观分类和免疫检查点基因表达相结合的生物标志物，以增加对免疫疗法有反应的患者数量。
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