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

• 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
• 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

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)通路的免疫调节剂表现出显著的作用 并构成了癌症治疗的新护理标准。这些代理商的成功应该归功于 与PD-1受体的显著免疫抑制功能及其选择性表达有关 肿瘤微环境(TME)中的配体PD-L1，可产生良好的药效毒性比。然而， 尽管抗帕金森病疗法取得了巨大的进步，但只有一小部分患者出现了长期反应， 说明了在TME中识别新的免疫调节剂的必要性，特别是在PD-L1阴性肿瘤中。至 为此，我们建立了第一个基因组规模的人膜蛋白T细胞活性筛选并鉴定 Siglec-15作为一种关键的免疫抑制因子，对多种癌症类型具有广泛的上调作用，并成为治疗癌症的新靶点 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 抑制性配体。除了肿瘤相关的巨噬细胞外，它在癌细胞上也有明显的表达，而且 在人类肿瘤中表现出PD-L1的互斥表达模式。单抗阻断Siglec-15的研究 抗体在小鼠肿瘤模型和人癌细胞培养系统中的治疗效果及结果 在放大的T细胞反应中。Siglec-15可能代表一类与肿瘤相关的新型免疫检查点配体- PD-L1的相关表达和不同作用机制在抗PD中的重要意义 反应迟钝的病人。基于这些结果，我们开发了一种抗人Siglec-15抗体(NC318) 相关的I/II期临床试验目前正在进行中，用于治疗PD-1难治性转移性实体癌。虽然 初步的临床试验结果相当有希望，清楚地阐明了免疫抑制 Siglec-15在肿瘤微环境中的作用机制将促进这一新程序的临床翻译。 除了调节T细胞功能外，我们的新发现还表明Siglec-15代表了一种潜在的新的 髓系细胞的控制轴，是塑造肿瘤微环境的关键免疫细胞亚群， 相对缺乏成功的临床靶点。除此之外，重要的问题仍然是优化Siglec-15- 相关治疗，如其受体(S)，诱导机制，以及潜在的相加效应或协同作用 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 免疫学和免疫疗法：1)确定Siglec-15超越T细胞的潜在免疫功能， 尤其是在髓系细胞上，并鉴定髓系细胞和T细胞上具有功能的Siglec-15受体； 2)研究致癌KRAS突变体在肿瘤中诱导Siglec-15表达机制的作用 使用两个癌基因KRAS突变相关的细胞并确定更好的抗Siglec-15联合疗法 同种异体原位小鼠胰腺癌和卵巢癌模型。总的来说，我们建议的研究将 促进我们理解一个新的PD-L1互斥免疫检查点并增强Siglec-15- 抗PD-1/PD-L1不敏感癌症的基础治疗方法。