CX3CL1

*仅供医学专业人士阅读参考调节肿瘤相关巨噬细胞（TAMs），改变不利于免疫应答的肿瘤微环境，这种给免疫治疗铺路的套路，可以说是百用不厌啦，而且对于肝细胞癌（HCC）之类免疫抑制性极强的实体瘤，多一个干预靶点就多一分抗癌希望。近日，中山大学附属第三医院黄月华、练一帆团队在Journal of Experimental & Clinical Cancer Research期刊发表的最新研究，就揭示了可通过表观遗传调节，减少HCC微环境中TAMs数量，有望增敏现有免疫治疗的靶点——钙周期素结合蛋白（CacyBP）[1]。该研究显示，CacyBP与人体内调节先天免疫的转导蛋白Myd88关系紧密，抑制CacyBP-Myd88信号轴可减少趋化因子CX3CL1的分泌，降低被募集到HCC免疫微环境中的TAMs数量，让HCC免疫微环境更有利于PD-1抑制剂治疗。论文首页截图黄月华、练一帆团队此前就曾揭示，CacyBP能够促进HCC的发生发展和侵袭，且这种作用与表观遗传有关[2]，本次研究则从HCC免疫微环境的角度切入：研究团队分析了139例HCC患者的肿瘤样本，发现HCC中普遍存在CacyBP和Myd88的上调（与正常肝脏组织相比），且CacyBP和Myd88蛋白之间存在相互作用。细胞实验显示，抑制CacyBP即可使Myd88蛋白水平下降，而过表达CacyBP则起到相反的作用，提示CacyBP与Myd88的水平正相关，但调节Myd88并不会影响CacyBP，这意味着Myd88是CacyBP的下游作用位点。借助外部数据库和免疫沉淀实验，研究者们证实CacyBP参与了由E3泛素连接酶Siah-1介导的Myd88降解：CacyBP与Siah-1间存在竞争关系，如果CacyBP先于Siah-1与Myd88发生相互作用，就能保护Myd88不被降解。而CacyBP对Myd88的保护，会使Myd88介导的下游信号通路更多地影响HCC免疫微环境；既往研究显示，Myd88可通过激活NF-κB通路，参与乙肝病毒慢性感染时肝脏内的免疫抑制[3]，但此次研究中并未观察到NF-κB通路下游响应基因（IL-6/CXCL8/TNF）的表达改变，说明CacyBP-Myd88信号轴的起效机制有所不同。借助二代测序（NGS）技术，研究者们找到了12条表达水平受敲低CacyBP或Myd88影响的通路，它们绝大多数都与免疫细胞迁移、细胞因子释放有关，如CX3CL1、CCL14和CCL15三种趋化因子的基因表达会显著下降，其中CX3CL1受到的影响最大；进一步实验证实，CacyBP-Myd88信号轴可调控CX3CL1基因启动子的组蛋白去乙酰化。敲低CacyBP-Myd88信号轴，可显著降低趋化因子水平而CX3CL1正是单核细胞衍生巨噬细胞被募集到肝脏的关键趋化因子[4]，CX3CL1水平下降了，TAMs在HCC中自然也就少了。研究团队分析了肿瘤浸润免疫细胞TIMER数据库的资料，发现CX3CL1及CacyBP、Myd88的表达水平，均与HCC中TAMs浸润总数，以及不利于抗肿瘤免疫应答的M2-TAMs总数正相关，初步验证了上述理论。对HCC患者肿瘤组织样本的分析也显示，CacyBP升高肿瘤中的M2-TAMs浸润明显较多，但CacyBP-Myd88信号轴并不会直接促使TAMs向M2型极化，它们只通过上调CX3CL1水平，使更多外周血中的单核细胞被募集到肿瘤部位；抑制CacyBP就可显著减少TAMs，进而与PD-1抑制剂治疗实现协同增效，显著改善对HCC的抑癌效果。抑制CacyBP可显著减少HCC中的TAMs数量，增敏免疫治疗本次研究的发现，可以说给CacyBP的促癌罪行添上了一条铁证，看来它既能直接促进HCC发生发展，又会参与抑制性免疫微环境的形成，接下来不妨就针对CacyBP开发精准治疗药物好了，HCC的系统性治疗毕竟还在起步期，理想的治疗药物越多越好啊~参考文献：[1]Wang J, Zhang X, Ma X, et al. Blockage of CacyBP inhibits macrophage recruitment and improves anti-PD-1 therapy in hepatocellular carcinoma[J]. Journal of Experimental & Clinical Cancer Research, 2023, 42: 303.[2]Lian Y F, Huang Y L, Zhang Y J, et al. CACYBP enhances cytoplasmic retention of P27Kip1 to promote hepatocellular carcinoma progression in the absence of RNF41 mediated degradation[J]. Theranostics, 2019, 9(26): 8392.[3]Li H, Zhai N, Wang Z, et al. Regulatory NK cells mediated between immunosuppressive monocytes and dysfunctional T cells in chronic HBV infection[J]. Gut, 2018, 67(11): 2035-2044.[4]Sun C, Hu A, Wang S, et al. ADAM17-regulated CX3CL1 expression produced by bone marrow endothelial cells promotes spinal metastasis from hepatocellular carcinoma[J]. International Journal of Oncology, 2020, 57(1): 249-263.本文作者丨谭硕

Initiated dosing of three patients in first cohort of Phase 1 clinical trial of QN-302 for treatment of advanced or metastatic solid tumorsPhase 1a patient recruitment ongoing; company anticipates sharing update on safety and preliminary efficacy in second quarter of 2024Expect to select lead Pan-RAS inhibitor candidate for IND enabling studies in first quarter of 2024 CARLSBAD, Calif., Nov. 14, 2023 (GLOBE NEWSWIRE) -- Qualigen Therapeutics, Inc. (Nasdaq: QLGN), a clinical-stage therapeutics company focused on developing treatments for adult and pediatric cancers with potential for Orphan Drug Designation, today provides a corporate update for the third quarter ending September 30, 2023 and to date: Highlights: QN-302 Announced first cohort of three patients initially dosed in the Phase 1 clinical trial of QN-302 for treatment of advanced or metastatic solid tumorsPresented scientific data on QN-302 at AACR Special Conference: Pancreatic Cancer, in October 2023: “The Pan G-Quadruplex experimental drug QN-302 in PDAC: identification of potential biomarkers for clinical studies” by Ahmed Ahmed, Tariq Arshad, and Stephen Neidle. Studies showed that increased expression of S100P and CX3CL1 correlated with human pancreatic ductal adenocarcinoma (PDAC) disease progression – both gene targets previously proposed as potential biomarkers (Poster). “Target genes in pancreatic cancer cells of the Pan G-Quadruplex clinical candidate compound QN-302 revealed by comparative transcriptome profiling” by Ahmed Ahmed, Tariq Arshad, Maria Roman-Escorza, Dan Neidle, and Stephen Neidle. Studies showed that administering QN-302 to PDAC cells produced significant changes in the pattern of down-regulated G-quadruplex (G4) genes (Poster). Partnered with TD2 for Phase 1 clinical development of QN-302 for the treatment of advanced or metastatic solid tumors. Pan-RAS Presented poster highlighting Qualigen Therapeutics’ Pan-RAS inhibitor platform at AACR Special Conference: Advances in Breast Cancer, in Oct 2023: “Pan-RAS Inhibitors to Treat Luminal B Breast Cancer” by Geoff Clark, Raphael N. Jigo, Howard Donninger. Our RAS inhibitors suppressed the interaction of RAS with its downstream mitogenic effectors and suppressed RAS signaling pathways (MAPK and RAL pathways) in Luminal B breast cell model systems (Poster). Dear Shareholders: In the third quarter to date this year, we completed our transition from a diversified life science company to a streamlined clinical stage therapeutics company focused on execution and judicious capital deployment toward our differentiated oncology pipeline for the benefit of patients worldwide. In July we announced the divestiture of our FastPack® diagnostics business for approximately $5 million in an all-cash transaction to support advancement of our therapeutics pipeline. Our team and collaborators have worked diligently to advance our QN-302 program on time and within budget. We are excited to announce the initiation of dosing of not only our first patient, but of our first cohort of three patients in the Phase 1a dose escalation portion of our clinical trial of QN-302, an investigational G4-selective transcription inhibitor. This follows the announcement of QN-302 receiving US FDA Investigational New Drug (IND) clearance to initiate the clinical trial in July and the announcement of first patient dosed last week. Our Pan-RAS inhibitor platform continues to present compelling in vivo data in multiple cancer models as we make progress toward identifying a lead candidate for IND-enabling studies under our sponsored research collaboration with the University of Louisville, Kentucky. About Our Phase 1 Clinical Trial for QN-302 As stated above, our focus in 2023 has been the swift execution of business priorities. We initiated IND-enabling studies for QN-302 in January 2022, when the technology package was exclusively in-licensed from the University College London, having been discovered and developed by Dr. Stephen Neidle’s group at the School of Pharmacy. We enlisted our CRO, TD2, and within 18 months of initiating IND-enabling studies we received IND clearance to initiate Phase 1 clinical trials by the US FDA. In January 2023 we obtained Orphan Drug Designation for the potential treatment of pancreatic cancer. Details of our Phase 1 study are as follows: Title: A Phase I, Multicenter, Open-label, Dose Escalation and Dose Expansion Trial Evaluating the Safety, Pharmacodynamics, and Pharmacokinetics of Intravenous QN-302 in Patients With Advanced or Metastatic Solid Tumors Pending the Company’s ability to secure additional capital, up to 36 patients will be enrolled in the dose escalation (Phase 1a) portion of the study. The exact number of patients to be enrolled will depend on the observed safety profile. The dose expansion (Phase 1b) cohort may enroll up to an additional 20 patients with advanced, metastatic solid tumors. The expansion cohort will further evaluate safety and assess for antitumor effect of QN-302. The primary objectives of this Phase 1a study are: To determine the MTD and the dose-limiting toxicities (DLTs) of QN-302 monotherapy in patients with advanced or metastatic solid tumors that have not responded to or have recurred following treatment with available therapies.To establish the dose of QN-302 recommended for future studies (the Recommended Phase 2 Dose [RP2D]). The secondary objectives of the Phase 1a study are: To determine the pharmacokinetics of QN-302.Explore the pharmacodynamic effects of QN-302 on selected tumor biomarkers.To observe patients for any evidence of antitumor activity of QN-302 by objective radiographic assessment. About Our Pan-RAS Inhibitor Platform We continue to build our data package for our lead optimization stage Pan-RAS inhibitor platform. Along with our team at the University of Louisville, we presented a poster in June at the American Society of Clinical Oncology’s (ASCO) 2023 Annual Meeting highlighting the ability of our pre-lead compounds to potentially overcome emerging resistance and limited clinical durability of commercially approved KRAS G12C inhibitors. This is an exciting development that we are actively exploring under our sponsored research agreement. More recently, in September our collaborator Dr. Geoff Clark presented at the American Association of Cancer Research: Advances in Breast Cancer Special Meeting describing data supporting how new pre-lead Pan-RAS candidates suppressed RAS signaling pathways (MAPK and RAL pathways) via anti-tumor activity in a breast cancer vivo model. We believe RAS continues to be a promising target. RAS is the most common cancer oncogene and activating mutations occur in one of the three human RAS gene isoforms (KRAS, HRAS, or NRAS) are present in about one-fourth of all cancers. In fact, mutant KRAS is found in 98% of pancreatic ductal adenocarcinomas, 52% of colon cancers, and 32% of lung adenocarcinomas. We believe a Pan-RAS inhibitor can complement other therapeutic approaches in development and are looking to advance potential partnerships for this compelling platform. Our goal is to select a lead compound for IND-enabling studies in the first quarter of 2024 and to present new data at major conferences throughout the year. We are proud of what our team and collaborators have accomplished in the third quarter this year and beyond. For the remainder of the fourth quarter and into 2024 our plan is to continue to execute and deploy capital judiciously on what we believe will be the highest return on investment activities without sacrificing quality, and most importantly, activities for patients who are relying on new therapeutic treatment options. We are encouraged by the feedback we have received at our two active clinical trial sites and welcome potentially adding additional sites next year. We plan to share updates with our QN-302 program and Pan-RAS inhibitor platform in Q1 next year, as well as provide an update on safety and preliminary efficacy for our Phase 1a study for QN-302 in the first half of 2024. Thank you again for your support. Sincerely,Michael S. Poirier, CEO, Chairman of the Board, and Founder About Qualigen Therapeutics, Inc. Qualigen Therapeutics, Inc. is a clinical-stage therapeutics company focused on developing treatments for adult and pediatric cancer. Our investigational QN-302 compound is a small molecule selective transcription inhibitor with strong binding affinity to G4s prevalent in cancer cells; such binding could, by stabilizing the G4s against “unwinding,” help inhibit cancer cell proliferation. The investigational compounds within Qualigen’s family of Pan-RAS oncogene protein-protein interaction inhibitor small molecules are believed to inhibit or block the binding of mutated RAS genes’ proteins to their effector proteins, thereby leaving the proteins from the mutated RAS unable to cause further harm. In theory, such mechanism of action may be effective in the treatment of about one quarter of all cancers, including certain forms of pancreatic, colorectal, and lung cancers. Forward-Looking Statements This news release contains forward-looking statements by Qualigen that involve risks and uncertainties and reflect the Company's judgment as of the date of this release. These statements include those related to the Company's prospects and strategy for development of its therapeutic drug candidates, including the anticipated timeline for the Company’s Phase 1 clinical trial and enrolling and dosing of patients (including possibly those with solid tumors), the sharing of initial data, the ability of the Company to raise additional capital, and the timing of selection of a lead compound for IND-enabling studies of Pan-RAS. Actual events or results may differ materially from the Company's expectations. There can be no assurance that the Company will be able to successfully develop any drugs (including QN-302, Pan-RAS and QN-247); that preclinical development of the Company's drugs (including Pan-RAS and QN-247) will be completed on any projected timeline or will be successful; that any clinical trials will be approved to begin by or will proceed as contemplated by any projected timeline, or at all; that any future clinical trial data will be favorable or that such trials will confirm any improvements over other products or lack negative impacts; that preclinical study results the Company observed in animals will be borne out in human patients; that any drugs will receive required regulatory approvals (or Fast Track designation or Orphan Drug status) or that they will be commercially successful; that patents will issue on the Company's owned and in-licensed patent applications; that such patents, if any, and the Company's currently owned and in-licensed patents would prevent competition; or that the Company will be able to procure or earn additional sufficient working capital to complete the development, testing and launch of the Company's prospective therapeutic products (including QN-302, Pan-RAS and QN-247). The Company's stock price could be harmed if any of the events or trends contemplated by the forward-looking statements fail to occur or is delayed or if any actual future event otherwise differs from expectations. Additional information concerning these and other risk factors affecting the Company's business can be found in the Company's prior filings with the Securities and Exchange Commission, including its most recent annual report on Form 10-K, all of which are available at www.sec.gov. The Company disclaims any intent or obligation to update these forward-looking statements beyond the date of this news release, except as required by law. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. For more information about Qualigen Therapeutics, Inc., please visit www.qlgntx.com. Contact:Investor Relationsir@qlgntx.com.Source: Qualigen Therapeutics, Inc.

该研究揭示了3次增强剂疫苗的独特特点，即在Omicron感染时通过“训练天然免疫”诱导单核细胞的活化和分化，从而提供保护性免疫。 截至2023年9月21日，全球新冠病毒SARS-CoV-2大流行已导致200多个国家和地区超过7.7亿例确诊病例及超过695万死亡病例，严重威胁了人类健康和公共卫生安全， 小范围的流行伴随新冠病毒进化和变异仍在不断发生。 一般认为，疫苗接种通过预先为宿主建立特异性抗病毒免疫记忆，从而起到预防病毒感染和病毒传播的作用。然而，新冠病毒（SARS-CoV-2） mRNA疫苗或/和灭活疫苗的免疫保护作用和免疫学机制尚未不明确。以往的研究关注新冠病毒mRNA疫苗或灭活病毒疫苗引发的针对Omicron变异株的特异性体液免疫和细胞免疫记忆的建立，灭活疫苗接种发挥的抗病毒作用是否涉及诱导“天然免疫记忆”，迄今为止尚不明确。 上海交通大学瑞金医院瞿介明教授、诸江教授、李庆云教授和陈赛娟院士合作，在 Cell 期刊发表了题为：Systemic immune profiling of Omicron-infected subjects inoculated with different doses of inactivated virus vaccine 的研究论文。 该研究以2022年春季上海Omicron变异株爆发为研究对象，建立了由接种了不同灭活病毒疫苗次数的感染者和未感染者组成的研究队列，通过整合质谱流式技术（CyTOF）、转录组测序（RNA-seq）和血浆微量蛋白的Olink检测技术和整合分析，揭示接种3次增强剂疫苗通过促进HLA-DRhigh经典单核细胞和非经典单核细胞的活化、Th1-like记忆效应性T细胞的极化，并抑制病理性调节性T细胞（Treg）的扩增等机制发挥免疫保护作用。相关性分析等研究提示：接种3次增强剂疫苗诱导了“训练天然免疫”，它会在Omicron感染时促进单核细胞的活化和成熟，而不是分化为髓源性抑制细胞（MDSCs）， 是一触发系例保护性免疫效应的核心事件。 该项研究首次系统性地描述了新冠病毒灭活疫苗接种对奥密克戎感染者免疫反应的影响，揭示了3次增强剂灭活疫苗通过诱导 “训练天然免疫”促进单核细胞的活化和成熟，从而发挥强有力抗病毒作用的分子机制。 通过CyTOF技术深入分析41个免疫细胞表面分子标志物的表达谱，鉴定了包括NK细胞、CD3+ T细胞、B细胞、树突状细胞、单核细胞和中性粒前体细胞在内共45个细胞亚群。在CD4+ T细胞亚群中，研究人员发现感染后3群naïve CD4+ T细胞的比例增加，而与未接种或接种2剂疫苗感染组相比，接种3剂疫苗感染组naïve CD4+ T细胞比例显著降低，提示3次增强剂疫苗可以促进CD4+ T细胞的活化。同时，Omicron感染后Treg细胞的比例及其TIM-3的表达增加，这一增加的趋势被3次增强剂疫苗接种所逆转。此外，感染后CD161hi效应记忆CD4+ T细胞和CD27int效应记忆CD4+ T细胞的比例下降，而接种3剂疫苗感染组与未接种或接种2剂疫苗感染组相比这两群细胞的比例上升。 这些结果表明，3次增强剂疫苗接种可以通过激活naïve CD4+ T细胞产生效应记忆CD4+ T细胞，而Omicron感染引起的Treg比例增加可能对此起到一定的限制作用。有趣的是，研究人员还通过实验证实3次增强剂疫苗接种在Omicron感染后促进CD4+ T细胞向功能性Th1方向极化，这已被证明对防止症状发生具有保护作用。在NK细胞亚群中，CD56hiCD16lo细胞因子分泌型NK亚群的比例在接种3剂疫苗感染组降低，而CD56intCD16hi细胞毒性NK亚群的比例在接种3剂疫苗感染组增加，提示3次增强剂疫苗可能会在Omicron感染后促进NK细胞成熟。 病毒感染的1-4天是一个主要由多种类型的天然免疫细胞的激活和功能主导的时期。在单核细胞方面，发现与健康对照组相比，Omicron感染者HLA-DRint经典单核细胞、HLA-DRhi经典单核细胞和非经典单核细胞的比例呈降低趋势。而与未接种组或接种2剂疫苗感染组相比，接种3剂疫苗感染组中HLA-DRhi经典单核细胞和非经典单核细胞的比例升高。同样地，Omicron感染后pDC细胞的比例降低同时及其PD-1和CTLA-4的表达增加，这一趋势被3次增强剂疫苗接种所部分逆转。由此可见，3次增强剂疫苗接种可以促进单核细胞/树突状细胞的活化和分化。 通过RNA-seq技术，进一步鉴定了一系列与免疫保护/免疫抑制密切相关的基因和信号通路。具体而言，单核/树突状细胞的功能激活而不是MDSC极化、Treg功能稳定性、记忆T细胞活化、Th1细胞分化、病毒复制抑制、低氧通路、TNF和NF-κB通路的活化，与接种3剂疫苗感染组正相关；而免疫缺陷、Th2细胞分化和线粒体代谢，与未接种组或接种2剂疫苗感染组相正相关。此外，与未接种组或接种2剂疫苗感染组相比，接种3剂疫苗感染组单核/巨噬细胞活或分化相关基因OSM、NAB2、THBS1、PLAUR、RAB20、ACSL1和TREM1，pDC激活基因SLC7A5和ICAM1，Treg功能稳定性基因DUSP5、SDC4、DUSP4、JAG1和PELI1，低氧通路基因JMJD6、VEGFA、HIF1A和NFIL3表达上调。相比之下，Treg增殖相关基因MCM3、CDC20和ZWINT，免疫抑制基因如T细胞免疫检查点受体BTLA以及NK细胞免疫检查点PVRIG和CISH，线粒体代谢基因LACTB2、ACADM、MRPS31和PYCR2在接种3剂疫苗感染组表达下调。这些结果表明，3次增强剂疫苗可能通过促进单核细胞/树突状细胞的活化和成熟，同时抑制致病性Treg的增殖，帮助宿主对抗Omicron感染。 BCG疫苗训练的天然免疫曾被提出作为增强对SARS-CoV-2感染的保护性免疫的可能手段。然而，灭活疫苗是否会诱导某些训练免疫通路，并在Omicron感染时再次发挥作用，这个问题尚未明确。研究人员分析了健康对照组和感染组中疫苗接种诱导的差异表达基因，发现在健康对照组中，大约1/5的疫苗接种诱导的基因在Omicron感染时也以相同的方向发生了差异表达，具有高度显著的相关性。为了筛选这33个同时上调和下调基因的核心基因，研究人员构建了这些基因的PPI网络，并揭示了排名前15的核心节点基因，其中包括调节单核细胞激活的基因如TREM1、C5AR1和FOSL1，其中TREM1已被证明是通过促进单核细胞活化从而发挥抗微生物感染的关键基因。有趣的是，这些同时上调和下调基因中的大多数（19/33），在外周血PBMC的26种免疫细胞类型中单核细胞中的表达最高。这些结果表明，在健康受试者接种疫苗后，通过预先训练，在Omicron感染后的某些关键单核细胞活化的驱动通路（如TREM1上调）可能会得到再次加强。 此外通过Olink技术系统检测了外周血血浆蛋白的变化，发现与与未接种组或接种2剂疫苗感染组相比，接种3剂疫苗感染组中细胞因子EN-RAGE、OSM和TGF-α水平上升，而CX3CL1水平显著下降。根据其他文献报道，EN-RAGE、OSM和TGF-α是促进单核细胞活化的关键细胞因子，而CX3CL1是促进免疫抑制性M2型巨噬细胞极化的趋化因子。此外，TNFSF14在接种3剂疫苗感染组中显著下降，而TNFSF14作为一种免疫共刺激分子，已被证明在抑制Treg积累和增殖方面发挥关键作用。 最后，研究团队对14个免疫细胞亚群（包括HLA-DRhi-经典单核细胞、非经典单核细胞、pDC、Treg、3群效应记忆CD4+ T细胞、3群naïve CD4+ T细胞、2群naïve-like T细胞、2群NK细胞）、13个基因（包含单核细胞激活和分化相关基因TREM1、ACSL1、CXCL16、PFKFB3、PLAUR、C15orf48、THBS1和NR4A3；Treg功能稳定性相关基因JAG1和LMNA；Treg扩增相关基因CDC20、ZWINT和MCM3）、3个基因集（2个与单核细胞活化相关和1个与Treg功能稳定性相关）、3种血浆蛋白（单核细胞活化相关蛋白OSM和EN-RAGE，Treg增殖相关蛋白TNFSF14）和9个临床参数（白细胞计数、中性粒细胞计数、抗RBD-总抗、抗RBD-IgG抗体、抗RBD-IgM抗体、抗WT或Omicron BA.2.2的中和抗体滴度、Ct值和尿素）进行Spearman聚类分析，所有这些因素在接种3剂疫苗感染组与未接种组或接种2剂疫苗感染组之间存在差异表达。根据它们之间的互相关系数，对这些组合因素（n=42）进行无监督聚类，形成了两个高度负相关的模块：其中较大的一个模块由三个子模块组成，富集了天然免疫激活、T细胞或NK细胞激活和体液免疫；较小的一个模块富集了Treg增殖。具体而言，在天然免疫激活子模块中，OSM、TNFSF14、白细胞和中性粒细胞计数、EN-RAGE、HLA-DRhi-经典单核细胞、非经典单核细胞和pDC之间的相关性更强，而与单核细胞活化和分化以及Treg功能稳定性有关的基因和通路之间的相关性更强。 总的来说，该研究揭示了3次增强剂疫苗的独特特点，即在Omicron感染时通过“训练天然免疫”诱导单核细胞的活化和分化，从而提供保护性免疫。 上海交通大学瑞金医院呼吸与危重症医学科瞿介明教授、瑞金医院上海血液学研究所诸江教授、呼吸与危重症医学科李庆云教授、转化医学国家重大科技基础设施（上海）陈赛娟院士为论文共同通讯作者。转化医学国家重大科技基础设施（上海）副研究员余山河，呼吸与危重症医学科主治医师林莹妮、副主任医师李勇；上海血液研究所博士研究生陈仕俊，呼吸与危重症医学科主治医师周丽娜、技师宋鹤杰为论文的共同第一作者。