CRTAM

引言 在人类免疫缺陷病毒（human immunodeficiency virus，HIV）感染中，CD8+T细胞对于病毒的清除至关重要【1】。因此，CD8+T细胞生物学动态与HIV感染患者息息相关。在慢性感染和肿瘤中，持续的抗原刺激诱导耗竭性T细胞（exhausted T cell，Tx）的产生【2】。TX的典型特征是由TOX等转录因子驱动的转录组和表观组重塑介导的效应功能减弱和抑制性受体的高表达【2】。值得注意的是，TOX不仅表达于Tx，也会表达于部分多功能效应记忆性T细胞，有时甚至与TCF-1共表达【3,4】，呈现干细胞样特性。研究表明，在大多数HIV感染患者中，HIV-特异性CD8+T细胞耗竭分子表达增加与高病毒载量和疾病进展相关【3,5】。在HIV感染患者外周血中，部分HIV-特异性CD8+T细胞中检测到TCF-1和TOX共表达【4】。作为HIV病毒存在和复制的主要位点，淋巴结内CD8+T细胞的表型和功能状态对于治疗策略的改善和设计至关重要。 近日，美国埃默里大学国家灵长动物研究中心微生物与免疫学部Mirko Paiardini研究团队在Nature Immunology杂志发表了题为Distinct SIV-specific CD8+ T cells in the lymph node exhibit simultaneous effector and stem-like profiles and are associated with limited SIV persistence的研究文章。这项研究通过流式、质谱、scRNA-seq和TCR-seq等分析在淋巴结内鉴定一群具有干细胞特性中间效应功能的SIV-特异性TOXhiTCF1+CD39+CD8+T细胞，该细胞倾向于淋巴滤泡定居并与靶细胞靠近，且能分化为终末效应细胞参与SIV病毒控制，为SIV/HIV感染提供新的免疫治疗靶点。 作者首先在恒河猴中建立猴免疫缺陷病毒（simian immunodefciency virus，SIVmac239）早期（42天）和晚期（17个月）感染模型。流式分析表明淋巴结CD8+T细胞内TOX表达随SIV感染时间延长而显著增加，尤其在CD95+记忆性CD8T细胞（memory CD8+T，TM）。与此同时，流式分析进一步发现淋巴结内 TOX+CD8+TM呈现GzmB+TCF-1-CD39+PD-1+TIGIT+TIM3+CD101+（传统效应T细胞，effector T, TEFF）和GzmK+GzmBlowTCF-1highCD39+PD-1+TIGIT+TIM3+CD101+两种。在未感染恒河猴中，淋巴结CD8+TM主要是TCF1+CD39-（占87%），而TCF1+CD39+只占6%；而在SIV早期感染淋巴结CD8+TM中，TCF1+CD39-占60%，TCF1+CD39+增加至27%；在晚期感染中，TCF1+CD39-降低至30%，而TCF1-CD39+TEFF占30%，TCF1+CD39+增加至40%。尽管TCF1+CD39+细胞群低表达细胞毒GzmB分子，但其与传统TCF1-CD39+TEFF细胞群有相似地活化脱颗粒能力。总之，这些数据表明SIV感染促进淋巴结CD8+T细胞TCF1-CD39+和TCF1+CD39+两种细胞群中TOX表达，虽然TCF1+CD39+细胞低表达细胞毒分子，但表现中间效应功能。 为了深入探究TCF1+CD39+CD8+TM功能，作者分离SIV感染恒河猴淋巴结内TCF1+CD39-、TCF1+CD39+和TCF1-CD39+CD8+TM并行质谱分析。结果证实TCF1+CD39+低表达细胞毒分子，包括perforin、GzmB和GzmA。此外，TCF1+CD39+细胞群高表达CD62L（T细胞迁移和淋巴结驻留相关）、CRTAM（淋巴结驻留）、DAP10、EOMES和IFNAR2（抗病毒相关）、NKG2C、NKG2D、CD94、CD160和GzmM（NK细胞毒相关以及T细胞增殖、扩增和功能相关）、CCL5（限制HIV感染）、ZHX3和PLK1（促增殖）和Bcl6（维持CD8细胞干性）。随后，作者分离早期SIV感染淋巴结中SIV特异性CD8+TM并行scRNA-seq分析，发现细胞分为C1（效应）、C2（干细胞样）、C3（增殖）、C4（IFN）和C5（其他）群。值得注意的是，TCF1+CD39+主要富集在C2群，表明干细胞样特性。TCR-seq分析指出TCF1+CD39+细胞群TCR克隆扩增，且主要克隆型与C1群重叠，表明TCF1+CD39+细胞群与TEFF存在线性关系。研究报道PD-1阻断促进干细胞样CD8+T细胞增殖和向TEFF分化【6】。作者发现PD-1抑制剂确实显著增加TCF1+CD39+CD8+TM和TCF1-CD39+TEFF比例，但Ki-67的增加仅在TCF1+CD39+CD8+TM细胞。这些结果表明TCF1+CD39+CD8+TM是一种有干细胞特性的中间效应细胞群，且具有向TEFF分化的能力。 随后，作者在SIV感染恒河猴中发现TCF1+CD39+CD8+TM的比例与血浆病毒载量以及淋巴结SIV DNA库呈负相关，表明其可以控制病毒和疾病进展。考虑到CD8+T细胞归巢至淋巴结滤泡与低病毒载量有关【7-9】，作者检测TCF+CD39+CD8+T细胞向淋巴结滤泡的迁移能力。首先，相比于TCF-CD8+T细胞，TCF-CD39+和TCF+CD39+CD8+T细胞CXCR5（滤泡归巢受体）表达显著增加，且TCF1+CD39+CD8+TM中CXCR5的表达同样与血浆病毒载量以及淋巴结SIV DNA库呈负相关，表明CXCR5对于TCF1+CD39+CD8+TM抗SIV的重要作用。其次，免疫荧光证实相比于TCF-CD8+T细胞，更多的TCF1+CD39+CD8+TM定位于B淋巴滤泡区，且与病毒RNA+CD4+靶细胞距离更近，表明TCF1+CD39+CD8+TM细胞具有更好的能力与感染CD4+靶细胞相遇以控制病毒。最后，作者在人HIV淋巴结样本中同样检测到TCF1+CD39+CD8+T细胞的存在。虽然低表达GzmB，但抗原刺激同样诱导脱颗粒和IFNγ表达，表明人HIV感染中TCF1+CD39+CD8+TM细胞可能具有类似的抗病毒能力。 综上所述，这项研究在猴和人缺陷免疫病毒感染淋巴结中鉴定一群具有干细胞样中间效应功能的TCF1+CD39+CD8+T细胞群，该细胞尽管缺乏经典细胞毒分子表达，但可以通过CXCR5定位于淋巴结滤泡区并与病毒感染CD4+T细胞作用，并继续分化为终末效应T细胞控制病毒载量，为促进TCF1+CD39+CD8+T扩增介导的病毒控制免疫治疗提供理论基础。 参考文献 1. David R, Collins., Gaurav D, Gaiha., Bruce D, Walker.(2020). CD8+ T cells in HIV control, cure and prevention. Nat Rev Immunol, 20(8), 0. doi:10.1038/s41577-020-0274-9 2. Christian U, Blank., W Nicholas, Haining., Werner, Held., Patrick G, Hogan., Axel, Kallies., Enrico, Lugli., et al. (2019). Defining 'T cell exhaustion'. Nat Rev Immunol, 19(11), 0. doi:10.1038/s41577-019-0221-9 3. Jean-Christophe, Beltra., Sasikanth, Manne., Mohamed S, Abdel-Hakeem., Makoto, Kurachi., et al. (2020). Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms. Immunity, 52(5), 0. doi:10.1016/j.immuni.2020.04.014 4. Takuya, Sekine., André, Perez-Potti., Son, Nguyen., Jean-Baptiste, Gorin., Vincent H, Wu., Emma, et al. (2020). TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Sci Immunol, 5(49), 0. doi:10.1126/sciimmunol.aba7918 5. David R, Collins., Jonathan M, Urbach., Zachary J, Racenet., Umar, Arshad., Karen A, Power., et al. (2021). Functional impairment of HIV-specific CD8+ T cells precedes aborted spontaneous control of viremia. Immunity, 54(10), 0. doi:10.1016/j.immuni.2021.08.007 6. Se Jin, Im., Masao, Hashimoto., Michael Y, Gerner., Junghwa, Lee., Haydn T, Kissick., Matheus C, et al. (2016). Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature, 537(7620), 0. doi:10.1038/nature19330 7. Morgan A, Reuter., Perla M, Del Rio Estrada., Marcus, Buggert., Constantinos, Petrovas., Sara, et al. (2017). HIV-Specific CD8(+) T Cells Exhibit Reduced and Differentially Regulated Cytolytic Activity in Lymphoid Tissue. Cell Rep, 21(12), 0. doi:10.1016/j.celrep.2017.11.075 8. Son, Nguyen., Claire, Deleage., Samuel, Darko., Amy, Ransier., Duc P, Truong., Divyansh, Agarwal., et al. (2019). Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8(+) T cells. Sci Transl Med, 11(523), 0. doi:10.1126/scitranslmed.aax4077 9. Constantinos, Petrovas., Sara, Ferrando-Martinez., Michael Y, Gerner., Joseph P, Casazza., Amarendra, et al. (2017). Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies. Sci Transl Med, 9(373), 0. doi:10.1126/scitranslmed.aag2285 https://doi.org/10.1038/s41590-024-01875-0 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

GAITHERSBURG, Md., July 30, 2024 (GLOBE NEWSWIRE) -- Today, Georgiamune Inc., a privately held, clinical-stage biotechnology company, announced that the first patient has been dosed with GIM-531 in a first-in-human, phase 1 clinical trial for the treatment of advanced cancer patients. GIM-531 development focuses on indications that are currently not addressed with existing or available immunotherapies including anti-PD-1 antibodies. It is an oral therapy that is a first-in-class selective T regulatory cell inhibitor. “The novel mechanism of action of GIM-531 can finally address one of the key challenges and limitations that has been facing the field in developing drugs selectively targeting suppressor immune cells like T-reg and sparing other important immune cells,” said Dr. Samir N. Khleif, Georgiamune founder and Chief Executive Officer. “This builds on Georgiamune’s ability to translate innovative research into novel therapies for patients with high unmet needs.” GIM-531 is a key part of Georgiamune’s rich pipeline of novel drugs. This news comes on the heels of announcing treating cancer patients with GIM-122, a dual functioning antibody. Both entered the clinic in less than a year from closing series A funding. “Our cancer patients need novel therapies beyond what’s currently available to them,” said Ryan Sullivan, M.D., medical oncologist at Massachusetts General Hospital. “We’re thrilled about the novel science that led to the development of GIM-531 and are excited to be part of this clinical trial using this promising first in class oral immunotherapy.” “The breadth of Georgiamune’s pipeline of assets for innovative cancer treatments and beyond is unmatched,” said John Connolly, PhD, chief scientific officer at the Parker Institute for Cancer Immunotherapy. “GIM-531 represents one of many new approaches that are being developed by Georgiamune expanding the potential treatment options for cancer patients with unmet needs.” The phase 1 trial will evaluate the safety profile, pharmacokinetics, and pharmacodynamic effects; as well as inform the dose, schedule and early anti-tumor activity of GIM-531 for patients with advanced solid tumors that have progressed on or have been intolerant of available therapies. Following the completion of the dose escalation, two additional study cohorts will be initiated for GIM-531, a single agent to be explored in a solid tumor where T-regulatory cells play an important role in the failure of the immune system to fight cancer and a combination with anti-PD-1 in anti-PD-1 failure advanced melanoma. “Although immune checkpoint inhibitors have transformed outcomes of several cancers, they do not work for many cancer types or cancers can develop mechanisms to evade their effectiveness. Therefore, there is a need for novel immunotherapies,” said Dr. Rizwan Khawaja, Associate Clinical Investigator at HonorHealth Research & Innovation Institute. “We are excited to participate in the first-in-human clinical trial of GIM-531. Novel immunotherapies like this can help expand treatment options for cancer patients and hopefully improve their prognosis.” About Georgiamune Inc.Georgiamune Inc. is a clinical-stage science and discovery biotechnology company focused on reprogramming immune signaling pathways to redirect the immune system to fight diseases. Georgiamune has designed unique approaches to re-establish immune balance, and its scientific discoveries have led to pioneering immunotherapies targeting high unmet needs. The company's lead program, GIM-122, is a first-in-class, dual-functioning monoclonal antibody. GIM-122 is designed to overcome immune therapy resistance in cancer patients. In addition to its lead program, the company is advancing a pipeline of first-in-class therapies for cancer and autoimmune diseases. Georgiamune was founded by Dr. Samir N. Khleif, a world-renowned medical oncologist and researcher in the field of immunology and cancer, based on discoveries in his lab on novel mechanisms to modulate immune response. Dr. Khleif's work has led to the discovery of novel core targets that control critical immune cell pathways leading to the development of first-in-class molecules that modulate and restore these immune signaling pathways for the treatment of cancer and autoimmune diseases. For more information about Georgiamune, please visit the company's website at Georgiamune.com or follow the company on LinkedIn. Media ContactKarbo Communications for Georgiamune georgiamune@karbocom.com

Georgiamune receives U.S. FDA clearance for GIM-531 and continues to enroll patients in clinical trial testing for GIM-122GAITHERSBURG, Md., May 29, 2024 (GLOBE NEWSWIRE) -- Today, Georgiamune Inc., a privately held, clinical-stage biotechnology company, announced the clearance of its second Investigational New Drug (IND) application by the U.S. Food and Drug Administration (FDA) for GIM-531, a first-in-class oral treatment that selectively targets T-regulatory cells and spares other immune cells such as CD4 and CD8. The news comes just on the heels of the company’s first-in-class, dual-functioning antibody, GIM-122, progressing to clinical trial for human testing. Since Georgiamune’s Series A funding round in August of 2023, the company has evolved from a preclinical stage startup to a company with two clinical assets. Both assets are first-in-class and boast a novel mechanism of action. GIM-122 overcomes cancer-mediated immune suppression and stimulates activated T cells while GIM-531 selectively inhibits the induction and function of T regulatory cells, reprogramming the tumor microenvironment to allow the elimination of the tumor cells. T regulatory cells are immune cells that play a critical role in inhibiting the immune response against cancer. Georgiamune’s development of the first-in-class, oral T regulatory cell inhibitor, allowing the restoration of a strong immune response against cancer, represents a rapid progression in translating innovative research into promising new treatment options for patients fighting cancer. With the clearance of the second IND, Georgiamune will be initiating a first-in-human clinical trial to investigate GIM-531 in areas of high unmet need, including cancers that are currently not addressed with existing immunotherapy drugs or available checkpoint inhibitors. “Georgiamune’s second IND clearance signifies the company’s achievement in pioneering novel breakthroughs for our extensive broad pipeline in both cancer and autoimmune diseases,” said CEO and founder Dr. Samir N. Khleif. “At a time when current cancer treatment options often fail to help patients who don’t respond to checkpoint inhibitors, Georgiamune is dedicated to creating novel drugs that address this critical unmet need. As a team, we take great pride in deploying GIM-531 and GIM-122 as part of our mission to revolutionize cancer treatment and patient care using novel science to reprogram the immune system.” “Georgiamune’s second IND clearance in less than a year is a testament to the depth of talent within the company, showcasing its capacity to spearhead what we believe are novel breakthroughs for first-in-class drug discovery for cancer patients around the world,” said Deep Nishar, Managing Director at General Catalyst. “Georgiamune’s therapeutic approach to cancer treatment aligns with our Health Assurance thesis, and we look forward to the company’s progress at its clinical trial stage.” About Georgiamune Inc.Georgiamune Inc. is a clinical-stage science and discovery biotechnology company focused on reprogramming immune signaling pathways to redirect the immune system to fight diseases. Georgiamune has designed unique approaches to re-establish immune balance, and its scientific discoveries have led to pioneering immunotherapies targeting high unmet needs. The company's lead programs, GIM-122 and GIM-531 are designed to overcome cancer-mediated immune suppression and selectively inhibits the induction and function of T regulatory cells. In addition to its lead programs, the company is advancing a pipeline of first-in-class therapies for cancer and autoimmune diseases. Georgiamune was founded by Dr. Samir N. Khleif, a world-renowned medical oncologist and researcher in the field of immunology and cancer, based on discoveries in his lab on novel mechanisms to modulate immune response. Dr. Khleif's work has led to the discovery of novel core targets that control critical immune cell pathways leading to the development of first-in-class molecules that modulate and restore these immune signaling pathways for the treatment of cancer and autoimmune diseases. For more information about Georgiamune, please visit the company's website at Georgiamune.com or follow the company on LinkedIn. Media ContactKarbo Communications PR for Georgiamune georigamune@karbocom.com