CNTN4

*仅供医学专业人士阅读参考作为人体内抗击癌症的主力军，理想状态下的CD8+T细胞应该是“闻战则喜”，见到癌细胞就化身虎狼之师开始杀伤才合理。但看了这么多年的科研，奇点糕只能说一句理想很丰满、现实超骨感了，更多时候的场面其实是癌细胞能把CD8+T细胞整“萎了”，而导致这种结果的调控机制当然也不止PD-1/L1通路，不然免疫检查点抑制剂们就不会时常碰壁了。近日，韩国研究者们在Science Immunology期刊发表的研究成果[1]，就揭示了癌细胞通过细胞接触反制理想状态下的又一重机制：人体内多种实体瘤都存在连接蛋白-4（CNTN-4）的过表达，它会与T细胞表面的淀粉样前体蛋白（APP）结合，抑制T细胞与癌细胞接合（conjugation）并下调T细胞激活状态，因此CNTN4-APP也是值得靶向的免疫抑制性通路。论文首页截图如果有读者对阿尔茨海默病（AD）比较熟悉，那应该不会对CNTN4和APP感到陌生，毕竟APP的全名就足够说明它和AD有着密切联系了，学界近年来对它们的研究也主要聚焦在神经科学领域[2]，这一下子跳到癌症还真是不小的跨界。但韩国研究者们的初步分析就显示，至少有13种实体瘤（共分析21种）组织的CNTN4强阳性（≥1+）率超过了50%。这么看来，该说是CNTN4在癌症领域被大家熟视无睹得太久了。研究者们随即敲除癌细胞的Cntn4或使其过表达，发现癌细胞增殖速率、迁移能力和侵袭性等关键特征并未显著改变，但过表达Cntn4会使癌细胞的凋亡通路和TNF-α等炎症应答通路显著下调；而用重组CNTN4蛋白处理激活T细胞，可直接抑制T细胞增殖和细胞因子分泌两大关键功能，效果甚至比重组PD-L1更强。CNTN4在多种实体瘤中存在过表达，且可抑制T细胞功能进一步的实验和染色质免疫沉淀（ChIP）分析显示，重组CNTN4抑制T细胞的机制主要是在T细胞激活时阻碍转录因子p65和NFATc1转位入核，结合到IFN-γ和TNF-α两大关键细胞因子的编码基因启动子部位，同时CNTN4还会通过抑制关键蛋白的磷酸化，干扰T细胞受体（TCR）信号级联，而研究者们专门开发的抗CNTN4单抗就可逆转上述过程。CNTN4抑制T细胞功能的罪行这就算实锤了，而实体瘤组织内过表达CNTN4的又是癌细胞，那T细胞表面肯定得有与CNTN4发生相互作用的受体，一个巴掌拍不响嘛。于是研究者们采用在人类质膜蛋白库中筛选的方法，找到了两种能与CNTN4结合的APP同源异构体（APP770/751），重组CNTN4与表达APP的T细胞结合，其实也就像PD-1/L1一样。而特异性敲除T细胞的App，就可显著增强T细胞对癌细胞的黏附能力、细胞毒性及T细胞本身的增殖能力，全方面上调抗肿瘤免疫应答，且APP和CNTN4在细胞外的相互作用可能对T细胞功能影响更明显；而以APP为靶标设计的单抗，也可以起到与抗CNTN4单抗相似的抑癌效果，这也和既有PD-1抑制剂、又有PD-L1抑制剂是同样的道理。抑制APP同样可增强抗肿瘤免疫应答最后，研究者们分析了胃癌、肺癌等常见实体瘤患者的数据，证实CNTN4表达水平与免疫激活标志物（GZMB、CXCL9/10等）及接受免疫治疗患者的生存预后大多呈负相关性，APP表达水平也与患者治疗应答有关，说明CNTN4-APP相互作用也有可能参与了当前免疫治疗的耐药，而抗CNTN4或抗APP单抗既可以与PD-1/L1抑制剂协同增效，也有望作为免疫后线治疗使用，特别是对CNTN4或APP高表达、当前预后可能较差的患者。CNTN4/APP表达水平当前的临床意义参考文献：[1]Jeon B N, Kim S, Kim Y, et al. Contactin-4 suppresses antitumor T cell responses by engaging amyloid precursor protein[J]. Science Immunology, 2024, 9(100): eadk7237.[2]Karuppan S J, Vogt A, Fischer Z, et al. Members of the vertebrate contactin and amyloid precursor protein families interact through a conserved interface[J]. Journal of Biological Chemistry, 2022, 298(2): 101541.本文作者丨谭硕

New research has shed light in the complex interplay between cell proteins, and how they impact on neurons in neurodevelopmental disorders and Alzheimer's disease. New research has shed light in the complex interplay between cell proteins, and how they impact on neurons in neurodevelopmental disorders and Alzheimer's disease. A new study led by the University of Exeter and published in Royal Society Open Biology has discovered the key role that the protein Contactin-4 (encoded by the gene CNTN4) plays in shaping neurons. The researchers began studying CNTN4 because it was known to have a role in autism, but its functional roles were not well understood. The team explored how CNTN4 functions within the brain, particularly its interactions with proteins involved in neurodegenerative diseases like Alzheimer's disease. For the first time, the researchers studied mice who have had the CNTN4 gene knocked out in the cortex, the region of the brain responsible for key functions including memory, thinking and reasoning. They found that neurons developed in a different way in the cortex region. Researchers have demonstrated for the first time in human cells the interaction between genes CNTN4 and APP, a gene strongly linked to Alzheimer's disease, revealing a co-dependent relationship that is essential for brain development, and specifically for the healthy growth of neurons. They found that CNTN4 not only contributes to neural elongation in the frontal cortex region of the brain, but also CNTN4 expression is regulated via a relationship with APP. Using studies in genetically modified human cells, the team also discovered that a complex interaction exists between CNTN4 and APP. If CNTN4 is knocked out, then levels of APP decrease, but not to zero. The scientists believe that APP may compensate for the loss of CNTN4, and vice versa. The study's lead author, Dr Rosemary Bamford, of the University of Exeter Medical School, said: "It was quite remarkable to discover that CNTN4, a gene linked to developmental processes, also plays a role in modulating factors involved in Alzheimer's disease. This intersection of developmental and neurodegenerative pathways offers exciting new insights into the broader implications of these proteins." Senior author Dr Asami Oguro-Ando, of the University of Exeter Medical School, said: "Looking ahead, my group is keen to further dissect the molecular mechanisms underpinning the interaction between CNTN4 and APP and explore their wider implications for disorders like Alzheimer's and Autism Spectrum Disorder. Our next steps involve clarifying how the CNTN4-APP interaction impacts neural activity. Understanding this interaction is crucial as it represents a fundamental step towards a comprehensive grasp of neurodevelopmental and neurodegenerative disorders."

- Lunit's AACR 2024 presentations to spotlight HER2 mutation insights and CNTN4's role in immunotherapy success, pioneering next-gen personalized treatment approaches, supported by the AI-powered Lunit SCOPE suite SEOUL, South Korea, April 1, 2024 /PRNewswire/ -- Lunit (KRX:328130.KQ), a leading provider of AI-powered solutions for cancer diagnostics and therapeutics, today announced the presentation of seven studies at the American Association for Cancer Research (AACR) 2024 Annual Meeting in San Diego, California, from April 5 to 10. Continue Reading Lunit to Showcase 7 Studies at AACR 2024 In a poster presentation, Lunit's AI-powered HER2 analyzer, Lunit SCOPE HER2's precision shines through its analysis of 194,259 pan-cancer samples, correlating different ERBB2 mutations with changes in HER2 protein expression. This AI-powered assessment successfully identified key mutation-expression correlations, particularly focusing on exon 20 insertions (ex20ins) and S310x mutations across a variety of cancers, including NSCLC, urothelial, and breast cancers. Through detailed HER2 intensity examination, the AI analysis highlighted that, among ERBB2-mutated cases with HER2 IHC images, a higher proportion of HER2 3+ tumor cells was observed in S310x and ex20ins cases compared to others. Similarly, high HER2 expression was observed in both S301x and ex20ins cases compared to other mutation cases. The findings suggest that understanding these mutation-expression relationships could improve the prediction of treatment responses, enabling a step forward in the development of more personalized and precise therapeutic strategies for cancer patients with ERBB2 mutations. The study also indicates the potential of AI in enhancing the precision of cancer treatment through the identification of genetic alterations that influence protein levels. In a collaborative study with Genome & Company, a clinical-stage biotechnology specializes in anti-cancer therapeutic development, Lunit leveraged its AI-powered immunohistochemistry (IHC) analyzer to investigate the expression of Contactin-4 (CNTN4) and its relationship with PD-L1 across 18 types of cancers. CNTN4, which is mainly expressed in tumor cells, is known to reduce T-cell activation and responsiveness to tumors. The analysis of 795 pan-cancer tissue samples revealed an important inverse correlation between CNTN4 expression and PD-L1 levels. When PD-L1 intensity was ≥ 30%, 50%, 75%, and 90%, CNTN4 was observed in 42.4% (337/795), 25.5% (203/795), 11.4% (91/795), and 5.2% (41/795) of cases, respectively. This insight positions CNTN4 as a promising target for immunotherapy, particularly in cancers that exhibit low PD-L1 expression. Another study conducted with Genome & Company focused on the correlation between the efficacy of pembrolizumab treatment and CNTN4 expression in gastric cancer patients. This study categorized patients based on CNTN4 and PD-L1 expression levels. The results indicated that patients with low CNTN4 expression and high PD-L1 levels were more likely to respond favorably to pembrolizumab, showing a 64.3% objective response rate (ORR). Conversely, patients exhibiting both high CNTN4 and PD-L1 expression demonstrated a 0% ORR, with non-responders presenting lower PD-L1 expression and higher CNTN4 levels compared to responders. These findings not only highlight CNTN4's potential as a predictive biomarker for immunotherapy response but also underscore the pivotal role of AI-powered analytics in identifying novel biomarkers. "We are excited to present our groundbreaking studies at AACR 2024, illustrating the profound impact of the Lunit SCOPE suite on cancer research and treatment," said Brandon Suh, CEO of Lunit. "Our findings, particularly the discovery of key mutation-expression correlations by Lunit SCOPE HER2 and the potential of CNTN4 as a novel biomarker for immunotherapy responsiveness, underscore our commitment to transforming cancer care. These studies not only highlight our pioneering role in leveraging AI to enhance precision medicine but also pave the way into the future of oncology - where treatment is not just personalized but predictive, ensuring the best possible outcomes for patients worldwide. We're proud to contribute to this transformative journey, marking a significant milestone in our mission to fight cancer with AI." In addition to the studies above, Lunit will present four more studies at this year's AACR, showcasing the diverse capabilities of Lunit SCOPE IO, Lunit SCOPE HER2, and an AI-based CT image analyzer combining analysis of CT scans with digital pathology analysis to predict response to checkpoint therapy. Visit Lunit at booth 808 to explore how the Lunit SCOPE suite is revolutionizing oncology research and clinical practice. Presentations at AACR 2024 featuring Lunit SCOPE include: "Pan-Cancer analysis of the influence of ERBB2 alteration on HER2 expression" (4640/16, Section 26, April 9, 9:00 AM - 12:30 PM) "Association of artificial intelligence (AI)-based HER2 scoring with clinical outcomes to first-line trastuzumab plus chemotherapy in HER2-positive metastatic gastric cancer (mGC)" (2484/1, Section 43, April 8, 9:00 AM - 12:30 PM) "Assessment of CNTN4 expression and its association with PD-L1 across 18 various cancers using an artificial intelligence-powered immunohistochemistry analyzer" (553/6, Section 23, April 7, 1:30 PM - 5:00 PM) "Association between the CNTN4 expression and responsiveness to pembrolizumab in gastric cancer" (7522/10, Section 42, April 10, 9:00 AM - 12:30 PM) "Artificial intelligence (AI)-based multi-modal approach using H&E and CT image for predicting treatment response of immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC)" (4170/25, Section 8, April 9, 9:00 AM - 12:30 PM) "Artificial intelligence-powered analysis of tumor-stroma ratio and fibroblast density as prognostic indicators in colorectal cancer" (276/7, Section 11, April 7, 1:30 PM - 5:00 PM) "Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as a prognostic biomarker for pembrolizumab plus chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma" (7658/19, Section 46, April 10, 9:00 AM - 12:30 PM) About Lunit Founded in 2013, Lunit is a deep learning-based medical AI company on a mission to conquer cancer. We are committed to harnessing AI to ensure accurate diagnosis and optimal treatment for each cancer patient using AI-powered medical image analytics and AI biomarkers. As a medical AI company grounded on clinical evidence, our findings are presented in major peer-reviewed journals, such as the Journal of Clinical Oncology and the Lancet Digital Health, and global conferences, including ASCO and RSNA. After receiving FDA clearance and the CE Mark, our flagship Lunit INSIGHT suite is clinically used in approximately 3,000+ hospitals and medical institutions across 40+ countries. Lunit is headquartered in Seoul, South Korea, with offices and representatives worldwide. For more information, please visit lunit.io. About Lunit SCOPE Lunit SCOPE is a suite of AI-powered software that analyzes tissue slide images for digital pathology and AI biomarker development, aiming to optimize workflow and facilitate more accurate and predictive clinical data for clinicians and researchers. Lunit SCOPE platform offers multiple AI-powered tissue analysis products and assays that can streamline digital pathology workflow and diagnostics and enhance the drug development process. Lunit SCOPE IO analyzes the tumor microenvironment (TME) based on H&E analysis and provides AI-based predictive clinical outcome information. In addition, AI-driven Immunohistochemistry (IHC) slide analysis services are offered through products such as Lunit SCOPE PD-L1, Lunit SCOPE HER2, Lunit SCOPE ER/PR, and others. SOURCE Lunit