NKG7

近日，同济大学附属上海市肺科医院姜格宁、张鹏教授团队开展的一项探索卡瑞利珠单抗联合化疗或阿帕替尼的新辅助治疗对初始不可切除NSCLC疗效的研究全文发表于《自然》子刊、国际知名医学期刊《Signal Transduction and Targeted Therapy》（STTT，IF=39.3） 1 。该研究探索了卡瑞利珠单抗联合治疗方案是否可以使更多初始不可切除非小细胞肺癌（NSCLC）患者有手术获益的机会。结果表明 1 ，卡瑞利珠单抗联合化疗组手术率为50.0%，卡瑞利珠单抗联合阿帕替尼治疗组手术率为42.9%，所有手术患者均实现了R0切除，有望为局部晚期NSCLC患者带来新的治疗策略。 研究文章发表于《Signal Transduction and Targeted Therapy》 研究背景 肺癌是全球发病和死亡人数最多的恶性肿瘤之一，其中非小细胞肺癌（Non-small cell lung cancer，NSCLC）占比约85% 2 。约半数NSCLC患者确诊时处于疾病早期或局部晚期 2 ，根据是否可手术完整切除，又进一步分为可切除、潜在可切除和初始不可切除疾病。对于初始不可切除NSCLC患者，目前标准治疗方案为同步放化疗加免疫巩固治疗。随着研究的深入，越来越多的证据表明 3-5 ，新辅助免疫联合治疗能显著提高可切除NSCLC患者的病理完全缓解（pCR）率和无事件生存期（EFS）。然而，新辅助免疫联合治疗能否将初始不可切除NSCLC转化为可切除状态，从而使该部分患者具备手术机会，仍缺乏前瞻性研究证据。 基于医学界对于初始不可切除NSCLC缺乏明确的定义这一临床问题，姜格宁、张鹏教授团队结合国内外专家共识及上海市肺科医院胸外科的经验，成立了多学科临床专家组（Multidisciplinary clinical team，MDT）共同制定了初始不可切除NSCLC的“肺科定义”：（1）肿瘤侵犯大血管、气管或主支气管等重要结构，术前评估判断诱导治疗降级后有以治愈为目的的切除机会的患者；（2）临床证实的淋巴结呈多站转移或巨块型融合，术前评估判断诱导治疗降级后能够耐受并进行肺门和纵隔淋巴结清扫术的患者；（3）术前评估认为即使行全肺切除，特别是右全肺切除，也有不能R0切除的可能。满足以上三个条件中任何一个即为初始不可切除NSCLC。 研究方法 从2020年9月29日至2022年6月29日，该研究共纳入51例初始不可切除的、EGFR及ALK阴性的Ⅱ-Ⅲ期初治NSCLC患者，其中30例接受卡瑞利珠单抗联合化疗（A组），21例接受卡瑞利珠单抗联合阿帕替尼治疗（B组）。经过2-4个周期新辅助治疗后，由多学科诊疗（MDT）评估为可切除的患者接受手术治疗，否则接受根治性放疗。主要研究终点为主要病理缓解（MPR）率。 研究结果 结果表明，A组手术率为50.0%（15/30），B组手术率为42.9%（9/21），所有手术患者均实现了R0切除。在手术患者中，A组的MPR率和pCR率均为20.0%，B组分别为55.6%和11.1%。两组患者的客观缓解率（ORR）分别为33.3%和55.6%。在22.4个月的中位随访期内，A组的中位EFS未达到，B组的中位EFS为16.8个月。安全性方面，与既往报道的新辅助免疫联合治疗相近。整个研究过程中未出现治疗相关死亡事件，无新辅助治疗相关手术推迟，无术后90天内死亡病例，整体安全性可控且可耐受。 新辅助免疫联合治疗后的病理缓解情况 此外，该研究还探索了对新辅助卡瑞利珠单抗联合阿帕替尼治疗敏感的生物标志物。通过对13例患者基线肿瘤样本的分析，研究者发现TYROBP在应答者中显著高表达，且其较PD-1和PD-L1具有更好的治疗应答预测效能（AUC=0.909），高表达TYROBP的患者具有更好的EFS和OS。这一发现在多个已发表的公开数据集中亦得到验证 6-9 。进一步的基因富集分析（Gene set enrichment analysis，GSEA）表明，“interferon gamma response”、“NK cell-mediated cytotoxicity”和“antigen processing and presentation”等通路在治疗应答者中显著富集。此外，应答者的肿瘤中有更高水平的免疫评分和CD8+T细胞浸润，且T细胞相关基因CCL5、NKG7亦显著高表达。提示TYROBP可能与治疗响应相关。 基线肿瘤样本RNA-seq探索对于治疗应答的生物标志物 研究总结 该研究首次明确定义了初始不可切除NSCLC，并初步证明了新辅助卡瑞利珠单抗联合化疗或阿帕替尼对该类人群疗效良好且安全性可控，将不可切NSCLC患者转化为可进行手术状态，从而有望为局部晚期NSCLC患者带来新的治疗策略。对生物标志物的探索表明，TYROBP可能是免疫联合阿帕替尼治疗应答的有效预测指标，有望指导临床筛选潜在获益人群。 参考文献： 1. Xia, H., Zhang, H., Ruan, Z. et al. Neoadjuvant camrelizumab (an anti-PD-1 antibody) plus chemotherapy or apatinib (a VEGFR-2 inhibitor) for initially unresectable stage II–III non-small-cell lung cancer: a multicentre, two-arm, phase 2 exploratory study. Sig Transduct Target Ther 9, 145 (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41392-024-01861-w. 2. Bourreau, C., Treps, L., Faure, S., Fradin, D. & Clere, N. Therapeutic strategies for non-small cell lung cancer: Experimental models and emerging biomarkers to monitor drug efficacies. Pharmacol. Ther. 242, 108347 (2023). 3. Forde, P. M. et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N. Engl. J. Med. 386, 1973-1985 (2022). 4. Wakelee, H. et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N. Engl. J. Med. 389, 491-503 (2023). 5. Lu, S. et al. Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial. JAMA. 331, 201-211 (2024). 6.Wu, P., Xiang, T., Wang, J., Lv, R. & Wu, G. TYROBP is a potential prognostic biomarker of clear cell renal cell carcinoma. FEBS Open Bio. 10, 2588-2604 (2020). 7.Jiang, J. et al. Identification of TYROBP and C1QB as Two Novel Key Genes With Prognostic Value in Gastric Cancer by Network Analysis. Front. Oncol. 10, 1765 (2020). 8.Shabo, I., Olsson, H., Stal, O. & Svanvik, J. Breast cancer expression of DAP12 is associated with skeletal and liver metastases and poor survival. Clin. Breast Cancer. 13, 371-377 (2013). 9.Dietrich, J., Cella, M., Seiffert, M., Buhring, H. J. & Colonna, M. Cutting edge: signal-regulatory protein beta 1 is a DAP12-associated activating receptor expressed in myeloid cells. J. Immunol. 164, 9-12 (2000). 声明： 1.本新闻旨在分享学术前沿动态，仅供医疗卫生专业人士基于学术目的参阅，非广告用途。 2.恒瑞医药不推荐任何未被批准的药品、适应症的使用。

本文为转化医学网原创，转载请注明出处 作者：Jerry 导读： 据报道，黏膜相关恒定T细胞(MAIT)具有调节肿瘤免疫的作用。然而，MAIT细胞在非小细胞肺癌(NSCLC)中的免疫特性及其与免疫检查点抑制剂(ICIs)疗效的相关性尚不明确。 5月3日，浙江大学/中南大学研究人员共同在期刊《Journal of Experimental & Clinical Cancer Research》发表了题为“CXCR6-positive circulating mucosal-associated invariant T cells can identify patients with non-small cell lung cancer responding to anti-PD-1 immunotherapy”的研究论文， 本研究表明CD8+MAIT细胞可能是对PD-1疗法有响应的NSCLC患者的潜在预测性生物标志物。CD8+MAIT细胞与免疫疗法敏感性的相关性可能归因于较高的CXCR6表达。 https://jeccr-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s13046-024-03046-3#Sec101 研究背景 01 肺癌仍然是全球癌症相关死亡的主要原因。根据2020年全球癌症统计数据，肺癌是第二大被诊断出的癌症类型。非小细胞肺癌（NSCLC）是最常见的肺癌类型，约占所有病例的85%。根据特定的组织学特征，NSCLC进一步分为三种亚型，包括腺癌、鳞状细胞癌和大细胞癌。 由于肺癌的高发病率和高死亡率，越来越多的研究试图探索新的治疗策略，包括免疫疗法。免疫疗法主要包括免疫检查点抑制剂（ICIs）、癌症细胞免疫疗法、癌症特异性疫苗和其他免疫系统调节剂。这是一种帮助免疫系统识别并消除癌细胞的癌症治疗方法。 程序性细胞死亡受体1 (PD-1)/程序性细胞死亡受体配体1 (PD-L1)检查点抑制剂是NSCLC患者常用的ICIs。然而，并非所有NSCLC患者都适合接受PD-1/PD-L1阻断治疗。肿瘤中PD-L1的表达是决定PD-1/PD-L1检查点抑制剂治疗NSCLC疗效的关键因素。然而，一些PD-L1低表达的患者对免疫治疗有良好应答，而另一些PD-L1高表达的患者则无应答。因此，确定明确的预测标志物以确定PD-1/PD-L1检查点抑制剂是否是合适的治疗方案非常重要。 研究进展 02 研究人员发现，99%的高表达CXCR6的CD8+MAIT细胞来自应答者。基于单细胞转录组轮廓，研究人员分析了CXCR6高表达和低表达CD8+MAIT细胞之间的差异表达基因。此外，研究人员进行了GO通路分析，以确定不同CXCR6表达水平的CD8+MAIT细胞中富集的信号通路相关基因。CXCR6高表达CD8+MAIT细胞中的差异表达基因显著富集在RNA降解过程、翻译起始、mRNA降解过程、核转录mRNA降解过程和终止密码子介导的降解过程中，而NF-κB翻译因子活性相关基因的正向调节在CXCR6低表达CD8+MAIT细胞中显著富集。细胞毒性评分分析证实，与CXCR6低表达CD8+MAIT细胞相比，CXCR6高表达CD8+MAIT细胞中具有显著富集的细胞毒性相关基因，包括CST7、GNLY、KLRG1、NKG7和PRF1。 接下来，研究人员研究了循环CD8+MAIT和CXCR6+CD8+MAIT细胞的水平是否能作为非小细胞肺癌（NSCLC）对抗PD-1疗法的响应的预测性生物标志物，影响临床预后。之后，研究人员研究了CXCR6的功能是否通过CXCL16-CXCR6轴介导。在这项研究中，研究人员基于单细胞RNA测序数据分析了参与CD8+MAIT细胞细胞间通信的配体-受体对。为了识别可能通过CXCL16-CXCR6对与CD8+MAIT细胞相互作用的循环细胞类型，研究人员通过细胞间相互作用分析了单细胞RNA测序转录组轮廓。 通过CXCR6-CXCL16轴，CD8+MAIT细胞在肺癌免疫治疗中的作用可能得以实现 研究结论 03 综上，本研究表明，CD8+MAIT亚群在免疫治疗响应的NSCLC患者的外周血中富集。CD8+MAIT细胞表达与免疫治疗敏感性的相关性可能归因于高水平的CXCR6表达 。因此，本研究首次阐明了外周血中的CD8+MAIT细胞可能是免疫治疗疗效的潜在预测性生物标志物。 参考资料： https://jeccr-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s13046-024-03046-3#Sec101 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

A pilot trial by investigators from Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, tested the nasal administration of the drug Foralumab, an anti-CD3 monoclonal antibody. Investigators found evidence that the drug dampened the inflammatory T cell response and decreased lung inflammation in patients with COVID-19. Further analysis showed the same gene expression modulation in patients with multiple sclerosis, who experienced decreased brain inflammation, suggesting that Foralumab could be used to treat other diseases. Their results are published in the Proceedings of the National Academy of Sciences. "We discovered a way to shut down inflammation not only seen in COVID-19, but also in a patient with multiple sclerosis as well as in healthy patients," said lead author Thais Moreira, PhD, an assistant scientist at the Ann Romney Center for Neurologic Diseases at BWH and an instructor in Neurology at Harvard Medical School. "This is very exciting because not only does our study suggest that this new monoclonal antibody drug is safe and can modulate the immune system without major side effects, but it can also decrease inflammation in multiple realms, so it may be useful for treating other diseases." "Inflammation is a major cause of many diseases," said senior author Howard Weiner, MD, founder and director of the Brigham Multiple Sclerosis Center and co-director of the Ann Romney Center for Neurologic Diseases. "Our center has spent decades looking for novel ways to treat disease where there is abnormal inflammation in a way that is safe and effective." In both COVID-19 and multiple sclerosis, the immune system is overactive. Foralumab, manufactured by Tiziana Life Sciences, is a drug that stimulates regulatory T cells of the immune system, or anti-inflammatory cells, resulting in decreased inflammation. This contrasts with other monoclonal antibodies previously given to treat or prevent symptoms of COVID-19 (such as Evusheld) that target the SARS-CoV-2 spike protein, which only had activity against specific variants and subvariants. In 2020, Moreira traveled to Brazil to carry out this study of Foralumab, which was given nasally to 39 patients with mild-to-moderate COVID-19 infections. Blood analysis showed signs that the patients who received 100ug of Foralumab each day for 10 days experienced less lung inflammation than their counterparts who did not. These findings led the team to carry out a sophisticated gene expression analysis to see how Foralumab was working to modulate the immune response in order to reduce inflammation. This revealed a pattern of three specific genes (NKG7, TGF beB1, and GIMAP7) involved with the anti-inflammatory effects of the drug, not only in the COVID-19 patients from the 2020 study, but also in a patient with multiple sclerosis at Brigham and Women's Hospital and in healthy volunteers as well. "This is the first nasal monoclonal antibody - other monoclonal antibody treatments were delivered intravenously and are no longer given as treatment because they are not effective against currently circulating viral variants," said Weiner. "Based on our studies, we expect that Foralumab may work on all variants as it acts on immune effects. This is promising for other diseases because it works on inflammation which is a major driver of many diseases." Given the limitations of the small sample sizes studied, the team is moving ahead with a placebo-controlled double-blind trial in progressive multiple sclerosis as well as planning a new trial to study long COVID. "Moreira's discovery of a common pathway and mechanism by which Foralumab modulates the immune system gives us a biomarker that we can use to monitor treatment," said Weiner. "Next, we are going to look at studying the use of Foralumab in long COVID, larger studies of multiple sclerosis, and other diseases such as Alzheimer's disease." Disclosures: H.L.W. is chair of the Scientific Advisory Board of Tiziana and received consulting fees and stock options from the company. T.C. is a member of the scientific advisory board and serves as a consultant to Tiziana Life Sciences. CMB-A serves as a consultant to Tiziana Life Sciences. T.G.M. and K.T.F.M. received consultation fees from Tiziana Life Sciences to monitor the clinical trials in which samples were used in this present work. In addition to providing Foralumab, Tiziana Life Sciences also provided financial assistance to the trial and immunological studies but did not participate in statistical analysis or data interpretation. G Moreira T, Gauthier CD, Murphy L, Lanser TB, Paul A, Matos KTF, Mangani D, Izzy S, Rezende RM, Healy BC, Baecher-Allan CM, Chitnis T, Kuchroo V, Weiner HL. Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19. Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2220272120. doi: 10.1073/pnas.2220272120