Tumor immune microenvironment dynamics and outcomes of prognosis in non-muscle-invasive bladder cancer.

IF 5.7 2区 医学 Q1 Medicine Cancer Science Pub Date : 2024-10-11 DOI:10.1111/cas.16333
Rei Kamitani, Nobuyuki Tanaka, Tadatsugu Anno, Tetsushi Murakami, Tsukasa Masuda, Yota Yasumizu, Toshikazu Takeda, Shinya Morita, Takeo Kosaka, Shuji Mikami, Kazuhiro Matsumoto, Mototsugu Oya
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Abstract

Agents that target PD-1 and PD-L1 have been developed in the treatment of bladder cancer (BC). However, the diversity of immune cell infiltration in non-muscle-invasive BC (NMIBC) and the dynamics of the microenvironment as it progresses to muscle-invasive/metastatic disease remains unknown. To assess tumor immune activity, hierarchical clustering was applied to 159 BC samples based on cellular positivity for the defined immune cellular markers (CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT), divided into two clusters. There was a "hot cluster" (25%) consisting of patients with a high expression of these markers and a "cold cluster" (75%) comprising those without. The expression of CD39, CD44, CD68, CD163, IDO1, and Ki67 was significantly higher in tumors in the hot cluster. Immunologically, high-grade T1 tumors were significantly hotter, whereas tumors that had progressed to muscle invasion turned cold. However, a certain number of high-grade NMIBC patients were in the cold cluster, and these patients had a significantly higher risk of disease progression. Using an externally available TCGA dataset, RB1 and TP53 alterations were more frequently observed in TCGA hot cluster; rather FGFR3, KDM6A, and KMT2A alterations were common in TCGA cold/intermediate cluster. Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy.

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非肌层浸润性膀胱癌的肿瘤免疫微环境动态和预后结果
针对 PD-1 和 PD-L1 的药物已被开发用于治疗膀胱癌(BC)。然而,非肌层浸润性膀胱癌(NMIBC)中免疫细胞浸润的多样性以及膀胱癌发展为肌层浸润性/转移性疾病时微环境的动态变化仍然未知。为了评估肿瘤免疫活性,研究人员对 159 个 BC 样本进行了分层聚类,根据细胞对定义的免疫细胞标记物(CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT)的阳性率将其分为两个群组。一个 "热群"(25%)是这些标记物高表达的患者,另一个 "冷群"(75%)是没有这些标记物表达的患者。热群肿瘤中 CD39、CD44、CD68、CD163、IDO1 和 Ki67 的表达明显较高。从免疫学角度看,高级别 T1 肿瘤明显偏热,而进展到肌肉侵犯的肿瘤则偏冷。然而,一定数量的高级别NMIBC患者属于冷群组,这些患者的疾病进展风险明显更高。利用外部提供的TCGA数据集,RB1和TP53的改变在TCGA热群中更为常见;而FGFR3、KDM6A和KMT2A的改变则常见于TCGA冷群/中间群。对卡介苗治疗后复发肿瘤的分析表明,肿瘤免疫活性在治疗前后广泛维持,在最初归入冷簇的肿瘤中,复发后检测到了高表达的FGFR3。总之,我们揭示了整个 BC 肿瘤微环境的动态变化,并确定了候选分子作为复发性 NMIBC(如卡介苗治疗后)的治疗靶点。
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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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