Tumor-immune hybrid cells evade the immune response and potentiate colorectal cancer metastasis through CTLA4.

IF 3.2 4区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Pariyada Tanjak, Amphun Chaiboonchoe, Thanawat Suwatthanarak, Kullanist Thanormjit, Onchira Acharayothin, Jantappapa Chanthercrob, Thammawat Parakonthun, Asada Methasate, Jared M Fischer, Melissa H Wong, Vitoon Chinswangwatanakul
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Abstract

Understanding the metastatic cascade is critical for the treatment and prevention of cancer-related death. Within a tumor, immune cells have the capacity to fuse with tumor cells to generate tumor-immune hybrid cells (THCs). THCs are hypothesized to be a subset of cancer cells with the capacity to enter circulation as circulating hybrid cells (CHC) and seed metastases. To understand the mechanism of THC metastasis, we investigated CHCs in peripheral blood from patients with stage IV colorectal cancer (CRC), as well as THCs in tissues of primary colorectal cancers and their liver metastasis sites using immunofluorescence, spatial proteomic, spatial transcriptomic, molecular classification, and molecular pathway analyses. Our findings indicated a high prevalence of CHCs and THCs in patients with stage IV CRC. THCs expressed CTLA4 in primary CRC lesions and correlated with upregulation of CD68, CD4, and HLA-DR in metastatic liver lesions, which is found in the consensus molecular subtype (CMS) 1 of primary CRC tissue. Pathway analysis of these genes suggested that THCs are associated with neutrophils due to upregulation of neutrophil extracellular trap signaling (NET) and neutrophil degranulation pathways. These data provide molecular pathways for the formation of THCs suggesting fusion with neutrophils, which may facilitate extravasation and metastatic seeding.

肿瘤免疫杂交细胞通过 CTLA4 逃避免疫反应并促进结直肠癌转移。
了解转移级联对于治疗和预防癌症相关死亡至关重要。在肿瘤内部,免疫细胞有能力与肿瘤细胞融合,生成肿瘤免疫混合细胞(THC)。据推测,THC 是癌细胞的一个亚群,有能力以循环杂交细胞(CHC)的形式进入血液循环,并播下转移的种子。为了了解 THC 转移的机制,我们采用免疫荧光、空间蛋白质组、空间转录组、分子分类和分子通路分析等方法研究了 IV 期结直肠癌(CRC)患者外周血中的 CHC,以及原发性结直肠癌及其肝转移部位组织中的 THC。我们的研究结果表明,在 IV 期 CRC 患者中,CHC 和 THC 的发病率很高。THCs在原发性CRC病变中表达CTLA4,并与转移性肝脏病变中CD68、CD4和HLA-DR的上调相关,这在原发性CRC组织的共识分子亚型(CMS)1中也有发现。这些基因的通路分析表明,THCs 与中性粒细胞有关,因为中性粒细胞胞外陷阱信号(NET)和中性粒细胞脱颗粒通路上调。这些数据为THCs的形成提供了分子途径,表明THCs与中性粒细胞融合,可能会促进外渗和转移播种。
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来源期刊
Clinical and Experimental Medicine
Clinical and Experimental Medicine 医学-医学:研究与实验
CiteScore
4.80
自引率
2.20%
发文量
159
审稿时长
2.5 months
期刊介绍: Clinical and Experimental Medicine (CEM) is a multidisciplinary journal that aims to be a forum of scientific excellence and information exchange in relation to the basic and clinical features of the following fields: hematology, onco-hematology, oncology, virology, immunology, and rheumatology. The journal publishes reviews and editorials, experimental and preclinical studies, translational research, prospectively designed clinical trials, and epidemiological studies. Papers containing new clinical or experimental data that are likely to contribute to changes in clinical practice or the way in which a disease is thought about will be given priority due to their immediate importance. Case reports will be accepted on an exceptional basis only, and their submission is discouraged. The major criteria for publication are clarity, scientific soundness, and advances in knowledge. In compliance with the overwhelmingly prevailing request by the international scientific community, and with respect for eco-compatibility issues, CEM is now published exclusively online.
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