TGF-β

引言 调节性T（Treg）细胞是免疫系统中的一种特殊T细胞亚群，负责维持免疫耐受性和防止自身免疫性疾病的发生。它们通过抑制过度的免疫反应，避免对自身组织发起攻击。Treg细胞特异性表达Foxp3转录因子，并通过分泌抑制性细胞因子（如IL-10和TGF-β）或直接与其他免疫细胞接触来抑制其活性【1】。Treg细胞在控制慢性炎症、预防自身免疫性疾病以及调节肿瘤微环境中都发挥着重要作用【2】。Treg细胞表达一系列表面受体，其中Lag3是一种类似于CD4的共受体，主要在活化的T细胞和Treg细胞中表达【3】。Lag3被认为是一种抑制性共受体，能够限制常规T细胞的增殖和IL-2的产生。有研究报道，Lag3缺陷的Treg细胞不能缓解自身免疫性脑脊髓炎，但是Lag3可能会限制自身免疫性糖尿病中Treg细胞的增殖和功能【4,5】。虽然Lag3对Treg细胞功能的调节已经被证实，但是Lag3调节Treg细胞的确切机制仍不清楚。 近日，来自美国西北大学范伯格医学院的Booki Min课题组在Immunity上发表了研究论文Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming。在本研究中，作者特异性突变Treg细胞的Lag3受体，揭示了Lag3通过PI3K-Akt通路抑制Myc的表达，从而支持Treg细胞免疫抑制功能的分子机制。 为了探究Lag3在Treg细胞功能调节中具体作用，研究人员在Lag3基因位点引入了loxP位点，将Lag3基因的1-3号外显子进行flox处理，然后与Foxp3CreYFP小鼠进行交配，构建了在Treg细胞中特异性缺陷Lag3的突变（Treg△Lag3E1-3）小鼠。通过诱导实验性自身免疫性脑脊髓炎（EAE），研究发现相较于野生型小鼠，Treg△Lag3E1-3小鼠的疾病进展更快且症状更严重，表现为中枢神经系统（CNS）中Treg细胞和CD4 T细胞浸润增加，促炎细胞因子也显著增加。这些结果表明，Lag3缺失的Treg细胞功能异常，未能有效控制EAE的发展。同时，研究人员还进一步的验证了Lag3在免疫抑制和肿瘤生长调控中的作用。总的来说，Lag3在维持Treg细胞的抑制功能和调节免疫反应方面发挥重要作用，其缺失可能导致更严重的炎症反应和免疫失调。 接下来，为了揭示Lag3调节Treg细胞功能的具体机制，研究人员先对CNS中分离的Treg细胞进行了RNA-seq分析。研究发现，代谢过程是Lag3缺失的Treg细胞中主要富集的途径。GSEA分析进一步确认，Lag3缺失的Treg细胞中上调的基因高度富集在细胞代谢途径中，包括Myc靶基因、氧化磷酸化、糖酵解和脂肪酸代谢途径。Myc是多种细胞代谢过程的关键调节因子，它直接激活几乎所有编码糖酵解酶的基因。在Lag3缺失的Treg细胞中，Myc表达高于对照组且与糖酵解相关的基因表达显著增加，与此相对应的是糖酵解活性增加。此外，在Lag3缺失的Treg细胞中敲低Myc的表达，糖酵解活性受到明显抑制，Treg细胞的免疫抑制功能得到恢复。研究人员还探究了Lag3抑制Myc表达的分子机制。他们发现Lag3胞质结构域缺失导致Myc及其代谢靶基因的过度表达，进而引发Treg细胞的代谢失调。这些结果表明，Lag3通过控制Myc的表达来调节Treg细胞的代谢和功能，Myc相关的代谢变化直接影响Treg细胞在体内的抑制功能。 研究人员还探究了Lag3抑制Myc表达的分子机制。他们发现Lag3胞质结构域缺失导致Myc及其代谢靶基因的过度表达，进而引发Treg细胞的代谢失调。之前的研究表明，PI3K-Akt信号通路在调控Myc表达中起重要作用，并且Lag3缺失在其他T细胞中能增强Akt磷酸化。因此作者推测Lag3可能通过PI3K-Akt信号通路抑制了Treg细胞中Myc的表达。为了证实这个推测，研究人员分析了Lag3缺失的Treg细胞中PI3K信号的激活情况以及使用PI3K-Akt通路的相关抑制剂处理细胞。结果表明，Lag3突变导致的PTEN下调、Rictor上调和Akt的异常磷酸化共同作用，引发Treg细胞的代谢失调和抑制功能减弱。当抑制PI3K和Rictor可以有效降低Myc的表达，恢复Lag3缺失的Treg细胞正常代谢活动，并改善其免疫抑制功能。 文章的最后，研究人员详细的分析了Lag3对Myc的调控是如何影响Treg细胞的代谢活动。前面介绍到Lag3的缺失会导致Treg细胞的糖酵解活性增强，一个显著特征是细胞外酸化率增加，而乳酸脱氢酶A（Ldha）是介导这种状况发生的关键基因，并且Ldha也是Myc的靶基因之一。因此，研究人员对Ldha的功能进行了分析。结果表明，Lag3缺失会导致Ldha的表达增加，这与Myc的表达升高相一致，乳酸分泌也随之增加。抑制Ldha的活性能够恢复Lag3缺失导致的Treg细胞功能障碍以及代谢异常，从而揭示了Myc-Ldha轴在Treg细胞功能中的关键作用。 模式图（Credit: Immunity） 总的来说，这篇文章揭示了Lag3共受体调节Treg细胞免疫抑制功能的具体机制，Lag3通过PI3K-Akt信号通路抑制Myc的表达，当Lag3缺失后Myc表达升高并激活下游代谢基因的表达，改写了Treg细胞的代谢进而影响了Treg细胞的抑制性功能。 参考文献 1. Sakaguchi, S., Yamaguchi, T., Nomura, T., and Ono, M. (2008). Regulatory T cells and immune tolerance. Cell 133, 775–787. 2. Vignali, D.A.A., Collison, L.W., and Workman, C.J. (2008). How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532. 3. Andrews, L.P., Marciscano, A.E., Drake, C.G., and Vignali, D.A.A. (2017). LAG3 (CD223) as a cancer immunotherapy target. Immunol. Rev. 276, 80–96. 4. Kim, D., Le, H.T., Nguyen, Q.T., Kim, S., Lee, J., and Min, B. (2019). Cutting Edge: IL-27 Attenuates Autoimmune Neuroinflammation via Regulatory T Cell/Lag3-Dependent but IL-10-Independent Mechanisms In Vivo. J. Immunol. 202, 1680–1685. 5. Zhang, Q., Chikina, M., Szymczak-Workman, A.L., Horne, W., Kolls, J.K., Vignali, K.M., Normolle, D., Bettini, M., Workman, C.J., and Vignali, D.A.A. (2017). LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes. Sci. Immunol. 2, eaah4569. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.immuni.2024.08.008 责编|探索君 排版|探索君 来源|BioArt End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

NORWOOD, Mass., Oct. 29, 2024 (GLOBE NEWSWIRE) -- Corbus Pharmaceuticals Holdings, Inc. (NASDAQ: CRBP) (“Corbus” or the “Company”), today announced that Yuval Cohen, Ph.D., Chief Executive Officer of Corbus, will participate in a fireside chat and one-on-one investor meetings at the Guggenheim Securities Healthcare Innovation Conference to be held November 11-13, 2024 in Boston, MA. Guggenheim Securities Healthcare Innovation ConferenceFormat: Fireside chat and one-on-one investor meetingsDate: November 12, 2024Time: 10:00 a.m. ETWebcast: Click here About Corbus Corbus Pharmaceuticals Holdings, Inc. is an oncology and obesity company with a diversified portfolio and is committed to helping people defeat serious illness by bringing innovative scientific approaches to well-understood biological pathways. Corbus’ pipeline includes CRB-701, a next generation antibody drug conjugate that targets the expression of Nectin-4 on cancer cells to release a cytotoxic payload, CRB-601, an anti-integrin monoclonal antibody which blocks the activation of TGFβ expressed on cancer cells, and CRB-913, a highly peripherally restricted CB1 receptor inverse agonist for the treatment of obesity. Corbus is headquartered in Norwood, Massachusetts. For more information on Corbus, visit corbuspharma.com. Connect with us on Twitter, LinkedIn and Facebook. Forward-Looking StatementsThis press release contains certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and Private Securities Litigation Reform Act, as amended, including those relating to the Company's trial results, product development, clinical and regulatory timelines, market opportunity, competitive position, possible or assumed future results of operations, business strategies, potential growth opportunities and other statement that are predictive in nature. These forward-looking statements are based on current expectations, estimates, forecasts and projections about the industry and markets in which we operate and management's current beliefs and assumptions. These statements may be identified by the use of forward-looking expressions, including, but not limited to, "expect," "anticipate," "intend," "plan," "believe," "estimate," "potential,” "predict," "project," "should," "would" and similar expressions and the negatives of those terms. These statements relate to future events or our financial performance and involve known and unknown risks, uncertainties, and other factors on our operations, clinical development plans and timelines, which may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Such factors include those set forth in the Company's filings with the Securities and Exchange Commission. Prospective investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this press release. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. All product names, logos, brands and company names are trademarks or registered trademarks of their respective owners. Their use does not imply affiliation or endorsement by these companies. INVESTOR CONTACT: Sean MoranChief Financial OfficerCorbus PharmaceuticalsSean.moran@corbuspharma.com Bruce MackleManaging DirectorLifeSci Advisors, LLCbmackle@lifesciadvisors.com

Strengthens Lyell’s clinical pipeline with the addition of IMPT-314, a dual-targeting CD19/CD20 CAR T-cell product candidate Data from ImmPACT’s multi-center Phase 1-2 clinical trial of IMPT-314 in patients with large B-cell lymphoma treated in the 3rd line CAR-naïve setting to be presented at a major medical conference later this year; initiation of a pivotal trial for IMPT-314 expected in 2025 Lyell has prioritized its pipeline to focus on next-generation CAR T-cell therapies, including IMPT-314 and LYL119, and is discontinuing development of LYL797, LYL845 and earlier-stage TIL programs Cash runway following the close of the transaction is expected to fund operations into 2027, through important clinical milestones for each pipeline program Lyell will host an investor webcast at 4:30 PM ET today Oct. 24, 2024 -- Lyell Immunopharma, Inc. (Nasdaq: LYEL) announced today that it has entered into a definitive agreement to acquire ImmPACT Bio USA Inc. (“ImmPACT”), a privately-owned clinical-stage biotechnology company. ImmPACT’s lead program, IMPT-314, is a CD19/20-targeting chimeric antigen receptor (CAR) T-cell product candidate that Lyell will continue to develop for hematologic malignancies, including large B-cell lymphoma. IMPT-314 was designed to outperform the efficacy of approved CD19 CAR T-cell therapies via a dual-targeting CAR T-cell design and to improve CAR T-cell persistence by enriching for naïve and central memory T cells during manufacturing. The acquisition of ImmPACT is expected to significantly strengthen Lyell’s clinical-stage pipeline of next- generation CAR T-cell therapies and complement its suite of proprietary technologies designed to generate longer-lasting, functional T cells to achieve more durable outcomes for patients with solid tumors and hematologic malignancies. “Lyell’s vision is to bring meaningful and durable clinical benefit to patients suffering from cancer with our next-generation cell therapies,” stated Lynn Seely, M.D., Lyell’s President and Chief Executive Officer. “The emerging data from ImmPACT’s ongoing Phase 1-2 trial and the Phase 1 clinical data from a published UCLA-sponsored trial suggest the potential of IMPT-314 to have improved complete response rates and duration of response compared to the approved CD19 CAR T-cell therapies in CAR-naïve patients with aggressive B-cell lymphoma. Since licensing this product candidate from UCLA, the team at ImmPACT has made impressive progress in the multi-center IMPT-314 Phase 1-2 clinical program. We look forward to presenting initial data from this program at a major medical conference later this year and initiating a pivotal trial for IMPT-314 in 2025.” “I am incredibly proud of the ImmPACT team and all of their accomplishments in developing next-generation CAR T-cell therapies,” stated Sumant Ramachandra, M.D., Ph.D., Chief Executive Officer of ImmPACT. “This transaction validates our novel science and enhances the potential for this therapy to make a meaningful impact on patients' lives. I am confident that in Lyell, we have found a team that shares our passion for advancing novel science to benefit patients.” ImmPACT licensed its dual-targeting CD19/CD20 CAR T-cell product candidate from the University of California, Los Angeles (UCLA). Phase 1 data in 13 patients with relapsed/refractory (R/R) aggressive non-Hodgkin lymphoma treated in a UCLA-sponsored clinical trial were presented at the 2024 AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy. CAR T-cell naïve patients with R/R diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma after at least two lines of therapy or mantle cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma after at least three lines of therapy were evaluated. Autologous T cells were obtained and enriched for CD14-/CD25-/CD62L+ naïve or memory T cells. Twelve out of 13 patients achieved a complete or partial response (92% objective response rate), with ten achieving a confirmed complete response (CR) (77% CR rate). The median progression-free survival was 50.1 months, and median overall survival was not reached with a median follow up of 32 months (range: 5.7 – not estimable). A favorable safety profile was observed. The ongoing Phase 1-2 clinical trial initiated by ImmPACT is a multi-center, open-label clinical trial designed to evaluate the tolerability and clinical benefit of IMPT-314 in patients with R/R aggressive B-cell lymphoma and determine a recommended Phase 2 dose. Initial Phase 1-2 clinical data evaluating IMPT-314 primarily in patients who have received at least two prior lines of therapy for large B-cell lymphoma will be presented at a major medical conference this year. IMPT-314 has received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of R/R aggressive B-cell lymphoma. Lyell expects to initiate a pivotal trial in 2025 for IMPT-314 in patients in the 3rd line setting who have not yet been exposed to CAR T-cell therapy. In connection with the acquisition, Lyell has prioritized its pipeline to focus resources on its most differentiated CAR T-cell clinical programs, including IMPT-314 following the close of the acquisition and LYL119. The enhanced anti-exhaustion technology incorporated into LYL119, including c-Jun overexpression, NR4A3 knockout, Epi-R and Stim R, has the potential to achieve improved efficacy at lower cell doses with an acceptable safety profile. In a validated in vivo preclinical model of non-small cell lung cancer, LYL119 achieved tumor control at a 10-fold lower cell dose than LYL797 with more gradual cell expansion to peak, and a substantial increase in the duration of cell killing demonstrated by a repetitive tumor cell killing assay in vitro. Lyell is discontinuing development of LYL797, its ROR1-targeted CAR T-cell product candidate to focus on the Phase 1 clinical trial of its next-generation ROR1-targeted CAR T-cell product candidate LYL119, which is expected to initiate enrollment of patients with platinum-resistant ovarian cancer or relapsed/refractory endometrial cancer this year or early next year. The LYL845 tumor-infiltrating lymphocyte (TIL) program is also being discontinued as the clinical data in patients with advanced melanoma did not meet our rigorous pre-determined criteria for continued development. Its next-generation TIL and rejuvenation programs that are in preclinical development will also be discontinued. Following the close of the transaction, Lyell expects its cash balance will fund operations into 2027, through important clinical milestones for each pipeline program, including initiation of a pivotal trial for IMPT-314, which is expected to start in 2025. Upon closing, Lyell will acquire worldwide rights to ImmPACT’s pipeline, including the next- generation bispecific CD19/CD20 autologous CAR T-cell therapy, currently in clinical development for B-cell lymphoma and autoimmune diseases, and an activating TGF-beta Claudin 18.2 CAR T-cell candidate, which is in preclinical development. Lyell will prioritize the development of IMPT-314 for patients with B-cell lymphoma. Deal terms include upfront consideration payable upon closing the potential transaction of $30 million in cash, subject to certain adjustments, and 37.5 million shares of Lyell common stock. ImmPACT shareholders will also be eligible to receive contingent consideration consisting of 12.5 million shares of Lyell common stock that may be earned upon the achievement of a value-enhancing clinical milestone and a low single-digit royalty on future net sales of the dual-targeting CD19/20 CAR T-cell product in the United States. The proposed transaction, which has been unanimously approved by the Boards of Directors of both companies, is expected to close in the fourth quarter of 2024. The closing of the proposed transaction is subject to expiration of the Hart-Scott-Rodino antitrust waiting period and the satisfaction of other customary closing conditions. Goldman Sachs & Co LLC is acting as sole financial advisor to Lyell in this transaction and Skadden, Arps, Slate, Meagher & Flom LLP is acting as its legal advisor. Cooley LLP is acting as ImmPACT’s legal advisor. Lyell’s management will host an investor conference call and Webcast beginning at 4:30 pm ET today. The Webcast can be accessed here. A replay of the event and presentation materials will be archived on the Investor page of the Lyell Website following the end of the event. Lyell is a clinical-stage company advancing a pipeline of next-generation CAR T-cell therapies for patients with solid tumors or hematologic malignancies. Lyell’s product candidates are enhanced with novel technology designed to generate T cells that resist exhaustion and have qualities of durable stemness in order to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical response. Lyell is based in South San Francisco, California with facilities in Seattle and Bothell, Washington. To learn more, please visit www.lyell.com. The content above comes from the network. if any infringement, please contact us to modify.