Elucidating the Immune Suppressive Mechanism of SIGLEC-15 in the Tumor Microenvironment

阐明 SIGLEC-15 在肿瘤微环境中的免疫抑制机制

基本信息

批准号：
10587743
负责人：
JUN WANG
金额：
$ 59.56万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587743
关键词：
Ablation Anti-CD40 Antibodies Binding Bioinformatics Biological Assay Cancer Model Cancer Patient Cell Culture System Cell physiology Cells Clinic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Data Databases Down-Regulation Ectopic Expression Exhibits Genetic Human Human Genome Immune Immunomodulators Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Infiltration Interferon Type II Interleukin-6 KRAS oncogenesis KRAS2 gene KRASG12D Knock-out Ligands Macrophage Macrophage Colony-Stimulating Factor Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Membrane Proteins Meta-Analysis Modeling Molecular Monoclonal Antibodies Mus Mutation Myelogenous Myeloid Cell Activation Myeloid Cells Organoids PD-1/PD-L1 Pathway interactions Patients Pattern Phase I/II Clinical Trial Phenotype Pilot Projects Refractory Regulation Reporting Resistance Role Safety Serous Shapes Signal Transduction Solid T cell response T-Lymphocyte TP53 gene Testing Therapeutic Toxic effect Treatment Efficacy Tumor Immunity Tumor-associated macrophages Up-Regulation anti-PD-1 anti-PD-1/PD-L1 antigen-specific T cells cancer cell cancer immunotherapy cancer therapy cancer type checkpoint receptors clinical translation combinatorial cytokine first-in-human genome-wide immune cell checkpoints immune checkpoint immune checkpoint blockade immune function immune modulating agents immunoregulation improved in vivo inhibitor insight mouse model mutant next generation novel novel strategies pancreatic cancer model patient subsets phosphatidylinositol 3-kinase gamma programmed cell death ligand 1 programmed cell death protein 1 programs receptor refractory cancer response selective expression sialic acid binding Ig-like lectin sialic acid receptor single-cell RNA sequencing small molecule inhibitor standard of care success synergism targeted treatment therapeutic evaluation transcription factor transcriptome sequencing treatment response tumor tumor growth tumor immunology tumor microenvironment tumorigenic

项目摘要

Immunomodulatory agents blocking the immune checkpoint PD-1/PD-L1 (PD) pathway have shown remarkable clinical benefits and constitute a new standard of care for cancer treatment. The success of these agents is due to the prominent immunosuppressive function of the PD-1 receptor alongside the selective expression of its ligand, PD-L1, in the tumor microenvironment (TME), leading to a favorable efficacy-to-toxicity ratio. However, despite the vast advances provided by anti-PD therapy, only a subset of patients develops a long-term response, illustrating the need for identifying new immune modulators in the TME, especially in PD-L1 negative tumors. To achieve this, we built the first genome-scale T-cell activity screen of human membrane proteins and identified Siglec-15 as a critical immune suppressor with broad upregulation on various cancer types and a new target for cancer immunotherapy. Siglec-15 has unique molecular features compared with many other known checkpoint inhibitory ligands. It shows dominant expression on cancer cells, besides tumor-associated macrophages, and exhibits PD-L1 mutually exclusive expression pattern in human cancers. Siglec-15 blockade by a monoclonal antibody shows therapeutic efficacy in mouse tumor models and human cancer cell culture systems and results in amplified T cell responses. Siglec-15 may represent a novel class of immune checkpoint ligands with tumor- associated expression and divergent mechanisms of action to PD-L1, with important implications for anti-PD unresponsive patients. Based on these results, we have developed an anti-human Siglec-15 antibody (NC318) with the related phase I/II clinical trials currently ongoing for PD-1 refractory metastatic solid cancers. Although the preliminary clinical trial results are quite promising, the clear elucidation of the immune suppressive mechanism of Siglec-15 in the tumor-microenvironment will advance the clinical translation of this novel program. Other than modulating T cell function, our new findings also suggest that Siglec-15 represents a potential novel axis of control for myeloid cells, a key immune cell subset critical in shaping the tumor microenvironment which have a relative lack of successful clinical targets. Beyond this, important questions remain to optimize Siglec-15- related therapy, such as its receptor(s), induction mechanisms, and potential additive effects or synergies with existing treatments. In this project, through two complementary aims, we will leverage our expertise in cancer immunology and immunotherapy to: 1) determine the potential immune function of Siglec-15 beyond T cells, particularly on myeloid cells, and to characterize functional Siglec-15 receptors on both myeloid cells and T cells; 2) examine the role of oncogenic KRAS mutants as induction mechanism of Siglec-15 expression on cancer cells and identify better anti-Siglec-15 combinatorial therapies using two oncogenic KRAS mutant-associated syngeneic orthotopic mouse models of pancreatic and ovarian cancer. Collectively, our proposed studies will facilitate our understanding of a novel PD-L1 mutually exclusive immune checkpoint and enhance Siglec-15- based therapeutic approaches for anti-PD-1/PD-L1 insensitive cancers.

阻断免疫检查点 PD-1/PD-L1 (PD) 通路的免疫调节剂已显示出显着的效果临床益处并构成癌症治疗的新护理标准。这些代理的成功归功于 PD-1 受体的显着免疫抑制功能及其选择性表达配体 PD-L1 存在于肿瘤微环境 (TME) 中，从而产生良好的功效/毒性比。然而，尽管抗PD疗法取得了巨大进步，但只有一小部分患者产生了长期反应，说明需要在 TME 中识别新的免疫调节剂，特别是在 PD-L1 阴性肿瘤中。到为了实现这一目标，我们构建了第一个基因组规模的人类膜蛋白 T 细胞活性筛选，并鉴定了 Siglec-15 作为一种关键的免疫抑制剂，对各种癌症类型具有广泛的上调作用，并且是治疗癌症的新靶点癌症免疫疗法。与许多其他已知检查点相比，Siglec-15 具有独特的分子特征抑制性配体。除了肿瘤相关巨噬细胞外，它在癌细胞上显示出显着表达，并且在人类癌症中表现出 PD-L1 相互排斥的表达模式。单克隆抗体对 Siglec-15 的阻断抗体在小鼠肿瘤模型和人类癌细胞培养系统中显示出治疗功效和结果放大的 T 细胞反应。 Siglec-15 可能代表一类新型免疫检查点配体，具有肿瘤作用 PD-L1 的相关表达和不同的作用机制，对抗 PD 具有重要意义无反应的患者。基于这些结果，我们开发了抗人Siglec-15抗体（NC318）目前正在进行针对 PD-1 难治性转移性实体癌的相关 I/II 期临床试验。虽然初步临床试验结果非常有希望，明确阐明了免疫抑制作用 Siglec-15 在肿瘤微环境中的作用机制将促进这一新项目的临床转化。除了调节 T 细胞功能外，我们的新发现还表明 Siglec-15 代表了一种潜在的新型药物髓样细胞的控制轴是一种关键的免疫细胞亚群，对于塑造肿瘤微环境至关重要相对缺乏成功的临床靶点。除此之外，优化 Siglec-15 仍然存在重要问题- 相关疗法，例如其受体、诱导机制以及潜在的附加效应或协同作用现有的治疗方法。在这个项目中，通过两个互补的目标，我们将利用我们在癌症方面的专业知识免疫学和免疫治疗：1) 确定 Siglec-15 除 T 细胞外的潜在免疫功能，特别是在骨髓细胞上，并表征骨髓细胞和 T 细胞上的功能性 Siglec-15 受体； 2) 检查致癌 KRAS 突变体作为 Siglec-15 表达对癌症的诱导机制的作用细胞并使用两种致癌 KRAS 突变相关物确定更好的抗 Siglec-15 组合疗法胰腺癌和卵巢癌的同基因原位小鼠模型。总的来说，我们提出的研究将促进我们对新型 PD-L1 互斥免疫检查点的理解并增强 Siglec-15- 基于抗 PD-1/PD-L1 不敏感癌症的治疗方法。