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.

免疫调节剂阻断免疫检查点PD-1/PD-L1（PD）途径已显示出显着的临床益处，构成了癌症治疗的新标准。这些代理商的成功应到期 PD-1受体的显着免疫抑制功能以及其选择性表达的表达配体PD-L1，在肿瘤微环境（TME）中，导致有利的疗效与毒性比。然而，尽管抗PD疗法提供了巨大的进步，但只有一部分患者会产生长期反应，说明需要鉴定TME中新的免疫调节剂，尤其是在PD-L1阴性肿瘤中。到实现这一目标，我们构建了人类膜蛋白的第一个基因组规模的T细胞活性屏幕并确定 SIGLEC-15是一种关键的免疫抑制剂，具有各种癌症类型的广泛上调，并成为癌症免疫疗法。与许多其他已知的检查点相比，Siglec-15具有独特的分子特征抑制配体。除了与肿瘤相关的巨噬细胞外，它在癌细胞上显示出显着的表达，并且在人类癌症中展示PD-L1互斥表达模式。 Siglec-15通过单克隆封锁抗体显示了小鼠肿瘤模型和人类癌细胞培养系统的治疗功效和结果在扩增的T细胞反应中。 Siglec-15可能代表具有肿瘤的新型免疫检查点配体相关的表达和发散机制与PD-L1的作用机制，对抗PD具有重要意义反应迟钝的患者。基于这些结果，我们开发了一种抗人Siglec-15抗体（NC318）当前正在进行的I/II期临床试验中，PD-1难治性转移性固体癌症。虽然初步临床试验结果非常有前途，对免疫抑制的明确阐明 Siglec-15在肿瘤微环境中的机制将推进该新型程序的临床翻译。除了调节T细胞功能外，我们的新发现还表明SIGLEC-15代表了潜在的新颖髓样细胞的控制轴，这是一个关键的免疫细胞子集，在塑造肿瘤微环境中关键相对缺乏成功的临床目标。除此之外，重要的问题仍然可以优化SIGLEC-15-- 相关疗法，例如其受体，诱导机制以及潜在的添加剂作用或与现有治疗方法。在这个项目中，通过两个补充目标，我们将利用我们在癌症领域的专业知识免疫学和免疫疗法：1）确定SIGLEC-15超出T细胞的潜在免疫功能，特别是在髓样细胞上，并表征髓样细胞和T细胞上的功能性SIGLEC-15受体； 2）研究致癌性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突变体相关的更好的抗Siglec-15组合疗法胰腺癌和卵巢癌的合成原位小鼠模型。总的来说，我们拟议的研究将促进我们对新型PD-L1相互排斥的免疫检查点的理解，并增强Siglec-15-- 抗PD-1/PD-L1不敏感癌症的基于治疗方法。