galectin-1

*仅供医学专业人士阅读参考肿瘤相关巨噬细胞（TAMs）是参与肿瘤微环境形成的重要免疫细胞，广泛存在于多种肿瘤中，具有显著的功能和表型异质性。研究表明，在肝细胞癌（HCC）中，TAMs通过抑制T细胞的募集和功能，促进肿瘤的生长、侵袭、转移以及治疗抵抗，其功能受肿瘤微环境中的分子调控[1]。肿瘤微环境常伴有脂质代谢异常。近日，复旦大学的林玉丽、黄晓武、徐延勇、杨旭光等人发表在《肝脏病学》期刊上的最新研究[2]，揭示了TAMs如何善用肝癌肿瘤微环境中的脂质代谢异常，加害于T细胞。他们发现，TAMs表达的脂肪酸结合蛋白5（FABP5），可以帮助TAMs处理肿瘤来源的不饱和脂肪酸，激活PPARγ信号通路，导致免疫抑制分子的上调，进而抑制T细胞的抗肿瘤免疫反应、促进肿瘤生长。FABP5缺失可显著增强T细胞的抗肿瘤作用，并提高肝癌免疫治疗的疗效。论文首页截图由于巨噬细胞的异质性，当前针对肿瘤相关巨噬细胞（TAMs）的治疗效果有限。探索不同表型TAMs在肿瘤中的具体作用，识别促肿瘤亚型，有助于开发更有效的TAM靶向抗肿瘤免疫疗法。在这项研究中，研究团队通过将致癌基因MYC和CTNNB1引入小鼠肝脏建立了HCC模型，并结合免疫细胞耗竭实验和单细胞RNA测序技术，发现肿瘤发展过程中TAMs会通过增强自身脂质代谢来发挥免疫抑制特性。进一步研究表明，TAMs中富含脂质的亚群以表达脂肪酸结合蛋白5（FABP5）为特征。在FABP5+TAMs中，可以观察到脂肪代谢相关通路上调，Cd274、Lgals1、Crlf2、Cd47等免疫抑制相关基因表达上调。而且CellChat分析结果指出，FABP5+TAMs与功能耗竭T细胞、调节性T细胞、记忆T细胞之间表现出增强的配体-受体相互作用，意味着这些Fabp5+TAMs通过与T细胞的直接相互作用来协调免疫抑制效应。Fabp5+TAMs的脂质代谢发生改变Fabp5+TAMs对T细胞如此打压，是因为收了肿瘤细胞的油水。一系列研究结果显示，HCC细胞的脂质代谢发生改变，释放更多的长链不饱和脂肪酸（例如DHA和油酸）到肿瘤微环境中。来自肿瘤细胞的不饱和脂肪酸被TAMs吸收后，会促进FABP5与过氧化物酶体增殖物激活受体γ（PPARγ）的结合，增强PPARγ在巨噬细胞中的转录活性，这会促使TAMs向免疫抑制型表型转变，上调PD-L1、GAL1等免疫抑制分子的表达，抑制T细胞的增殖和功能。Fabp5+TAMs处理来自肿瘤细胞的脂肪酸后抑制T细胞功能如果敲除巨噬细胞中的FABP5，可以显著抑制HCC小鼠的肿瘤生长，并增强PD-1抑制剂治疗的效果。在缺乏FABP5的巨噬细胞小鼠模型中，肿瘤缩小且生存率提高。尤其在接受PD-1抑制剂（索拉非尼）治疗的小鼠中，抗肿瘤免疫反应显著增强，具体表现为CD4+、CD8+T细胞和NK细胞的肿瘤浸润和增殖能力增加，表达IFN-γ和颗粒酶B的T细胞占比提高。同时，缺乏FABP5的巨噬细胞的抗原处理能力也得到增强，IL-10、TGF-β等免疫抑制分子表达减少。此外，巨噬细胞的FABP5表达缺陷还能够有效逆转小鼠脂肪肝相关的HCC进展，并增强T细胞介导的抗肿瘤免疫反应。为验证以上结果的临床转化价值，研究团队对癌症基因组图谱计划（TCGA）数据集和近200名患者的数据进行分析。结果显示，FABP5在肝癌、胆管癌、宫颈癌和胰腺癌等多种肿瘤类型中mRNA表达水平升高，而且与正常组织相比，代谢功能障碍相关脂肪性肝病（MASLD）患者和脂肪肝病患者的病灶中FABP5+巨噬细胞数量也增加。与小鼠实验结果一致，表达FABP5的巨噬细胞表现出脂质代谢增加和免疫抑制特征，并且较高水平与HCC患者的较差总生存期呈正相关。与正常肝组织相比，HCC患者和脂肪肝病患者的病灶中FABP5+巨噬细胞数量增加，与生存有关该研究揭示了表达FABP5的巨噬细胞在肝细胞癌中的免疫抑制机制，并为通过靶向FABP5改善肿瘤免疫治疗效果提供了有力的依据。通过阻断FABP5或抑制肿瘤代谢不饱和脂肪酸，或许能够减少肿瘤微环境中的免疫抑制，进而增强PD-1抑制剂等免疫疗法的疗效，未来有望应用于改善肝癌及其他脂质代谢异常相关肿瘤的治疗。参考文献：[1]Pan Y, Yu Y, Wang X, Zhang T. Tumor-Associated Macrophages in Tumor Immunity. Front Immunol. 2020 Dec 3;11:583084. doi: 10.3389/fimmu.2020.583084. Erratum in: Front Immunol. 2021 Dec 10;12:775758. doi: 10.3389/fimmu.2021.775758. PMID: 33365025; PMCID: PMC7751482.[2]https://www.journal-of-hepatology.eu/article/S0168-8278(24)02569-8/abstract本文作者丨张艾迪

FROM ACF EQUITY RESEARCH HEALTHCARE TEAM NASDAQ: BCLI READ ACF EQUITY RESEARCH'S INITIATION NOTE HERE READ ACF EQUITY RESEARCH'S RELATED THEMATIC RESEARCH NOTE ON REGENERATIVE MEDICINE – NEURODEGENERATIVE DISEASE STEM CELLS & ALS/MND/LOU GEHRIG'S HERE LONDON, June 14, 2024 /PRNewswire/ -- INITIATION NOTE: BrainStorm Cell Therapeutics Inc. (Nasdaq: BCLI) is focused on developing autologous mesenchymal stem cell (MSC) therapies for the treatment of neurodegenerative diseases (NDDs) – BCLI's primary target is the fatal amyotrophic lateral sclerosis (ALS/MND/Lou Gehrig's). Post hoc analysis of BCLI's PIII trial data shows BCLI's NurOwn® (debamestrocel, MSC-NTF), has statistically significant clinical effects on early-stage ALS sufferers and that placebo trialists deteriorate faster. Peer reviewed research (Mar 2024) indicated that BCLI's NurOwn® has a positive impact on NfL biomarkers for ALS. These and other factors have persuaded the FDA to sign up to the SPA binding commitment for a NurOwn® PIIIb ALS trial. BCLI has regained regulatory minimum value NASDAQ compliance. Our valuation captures only the smaller by patients US market and excludes the larger EU/UK market. Post hoc analysis of BCLI's PIII early stage (mild-moderate) ALS sufferers (baseline ALSFRS-R scores >=35) treated with BCLI's NurOwn® (debamestrocel, MSC-NTF) revealed positive clinical responses with respect to slowing of ALS disease progression (primary endpoint). However the PIII trial cohort consisted (unexpectedly) of 23% advanced ALS sufferers, clouding the primary and secondary end point statistical analysis (possible floor effects). The new PIIIb trial is designed to recruit a cohort of participants with ALSFRS-R scores >=35. Additionally, more recent peer reviewed research found that certain biomarkers involved in ALS pathology, specifically NfL, LAP and Galectin-1 were found to be predictive of positive clinical outcomes in NurOwn® (debamestrocel, MSC-NTF),-treated participants. If the new trial design is successfully executed, as we forecast, we expect a strongly positive valuation inflection point for BCLI. ALS: High Unmet Medical Need Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder (NDD) that affects motor nerve cells in the brain and the spinal cord. There are an estimated ~450k ALS patients worldwide (30k US and 51k European). Median survival post diagnosis is 2 to 5 years. Current treatment options have very limited efficacy. Tofersen addresses just 2% of ALS sufferers. There is a high unmet need to slow/reverse ALS progression. SUBSCRIBE TO ACF EQUITY RESEARCH to receive notifications of new research products and services for investors. Visit our website to find out more. DISCLOSURES: ACF Equity Research has received cleared funds in advance for a minimum one year service directly from the issuer, from an exchange, from a portfolio manager; from an investor group or and from an investor relations firm. ACF Equity Research has received for any of investment/equity/credit/ESG/sustainability research a fixed paid in full in advance annual fee in the range US$35,000 to US$75,000 service package dependent. SOURCE ACF Equity Research

The protein galectin-1 (Gal-1) has been identified as a new PET imaging biomarker for immune checkpoint blockade (ICB) therapy, allowing physicians to predict the tumor responses before beginning treatment. Information garnered from Gal-1 PET imaging could also be used to facilitate patient stratification and optimize immunotherapy, enabling targeted interventions and improving patient outcomes. The protein galectin-1 (Gal-1) has been identified as a new PET imaging biomarker for immune checkpoint blockade (ICB) therapy, allowing physicians to predict the tumor responses before beginning treatment. Information garnered from Gal-1 PET imaging could also be used to facilitate patient stratification and optimize immunotherapy, enabling targeted interventions and improving patient outcomes. This research was published in the May issue of The Journal of Nuclear Medicine. Immunotherapies, such as ICB, have produced promising clinical outcomes in melanoma, non-small cell lung cancer, and several other types of tumors. However, only a subgroup of patients experiences positive outcomes with objective response rates spanning between five and 60 percent. "Developing reliable approaches for assessing responses and selecting eligible patients for immunotherapy remains challenging," said Zhaofei Liu, PhD, Boya Distinguished Professor at Peking University in Beijing, China. "Current clinical criteria for monitoring solid tumor responses to immunotherapy are based on CT and MRI scans, but these methods result in a considerable delay between treatment commencement and response evaluation. Molecular imaging techniques, especially PET, have emerged as robust tools for predicting immunotherapy effectiveness through the real-time, quantitative, and noninvasive assessment of biomarkers in vivo." In the study, a mouse model was utilized to identify new imaging biomarkers for tumor responses to ICB therapy. Through a proteomic analysis (separation, identification, and quantification of proteins in a tumor), researchers found that tumors exhibiting low Gal-1 expression responded positively to ICB therapy. Next, Gal-1 was labeled with 124I and the radiotracer (124I-α-Gal-1) and small animal PET imaging and biodistribution studies were conducted to assess the specificity of the radiotracer. PET imaging with 124I-αGal-1 showed the immunosuppressive status of the tumor microenvironment, thus enabling the prediction of ICB resistance in advance of treatment. For tumors that were not predicted to respond well to ICB therapy, researchers developed a rescue strategy that utilized a Gal-1 inhibitor that significantly improved the chance for success. "Gal-1 PET opens avenues for the early prediction of ICB efficacy before treatment initiation and facilitates the precision design of combinational regimes," noted Liu. "This sensitive approach has the potential to achieve individualized precision treatment for patients in the future." This research was published online in March 2024.