Leveraging B cell specificities for tumor glycans to elicit potent anti-tumor immunity

利用 B 细胞对肿瘤聚糖的特异性来引发有效的抗肿瘤免疫

基本信息

批准号：
10662537
负责人：
Karen M Haas
金额：
$ 41.39万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
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：
2022-07-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662537
关键词：
Acetylgalactosamine Adjuvant Adoptive Cell Transfers Antibodies Antibody Response Antigens Antitumor Response B-Lymphocyte Subsets B-Lymphocytes Binding CD4 Positive T Lymphocytes Carbohydrates Cell Communication Cells Circulation Complement Complement Inactivators Data Development Flow Cytometry Fostering Goals Human Immune response Immunoglobulin M Knowledge Link Malignant Neoplasms Monoclonal Antibodies Mucins Mus Neoplasm Metastasis Normal Cell Pathway interactions Patients Peptides Phenotype Play Polysaccharides Population Prognosis Recombinant Antibody Regulation Role Serine Shapes Specificity Spleen Supporting Cell T cell response T-Lymphocyte Testing Threonine Tn antigen Translating Tumor Immunity Tumor Promotion Tumor-Associated Carbohydrate Antigens Vaccines Vertebral column Work adaptive immune response anti-tumor immune response cancer cell cancer therapy cell killing glycosylation immunogenic immunomodulatory strategy in vivo interest mouse model neoplastic cell novel programmed cell death protein 1 receptor response targeted cancer therapy therapeutic target treatment strategy tumor tumor growth tumor specificity

项目摘要

SUMMARY Tumor associated carbohydrate antigens (TACAs) are aberrant glycosylation products that are expressed on cancer cells but absent on most normal cells. Their expression is typically associated with metastasis, poor prognosis, and reduced overall survival. Tn antigen (N-acetylgalactosamine O-linked to a serine or threonine) is a TACA often found on cancer mucins. We have investigated the regulation of B cell responses to Tn- and other TACA-bearing mucins using a mouse model. Our progress has shown that specificities for TACAs, including Tn, are highly enriched in the innate B (B1) cell population in mice. We have also found that B cell-intrinsic PD-1 expression potently suppresses tumor-protective TACA-specific antibody (Ab) responses and that CD4+ cells are required for the increased responses that are observed in the context of PD-1 inhibition. Finally, we identified a Tn-specific IgM monoclonal Ab that has significant and broad anti-tumor activity in vivo. Our understanding of the mechanisms regulating Ab responses to Tn and other TACAs is very limited. Similarly, our understanding of the mechanisms by which these Abs effectively kill cancer cells is incomplete. These critical gaps in knowledge must be filled in order to harness the protective capacity of TACA-reactive B cells and the Abs that they produce. The central hypothesis of this proposal is that B cells with natural specificities for TACAs play a critical role in the effective anti-tumor immune response to cancers. Our key objectives are to: 1) Determine the mechanisms by which CD4+ T cells support TACA-specific Ab responses and the extent to which PD-1 inhibition alters the diversity of the Tn-specific B cell response (Aim 1), 2) Identify the mechanisms by which Tn-specific IgM promotes both tumor cell killing and adaptive anti-tumor immune responses (Aim 2), and 3) Examine the repertoire of Tn-specific B cells in humans and identify broadly reactive Tn-specific Abs with tumor-killing potential (Aim 3). The findings emanating from these studies are expected to reveal novel opportunities to 1) harness the anti-tumor potential of B cells with specificities for cancer-expressed glycans and 2) leverage broadly-reactive TACA Abs for their ability to promote highly specific adaptive and dynamic immune responses targeting TACA-associated peptides.

概括肿瘤相关碳水化合物抗原 (TACA) 是异常糖基化产物，表达于癌细胞，但大多数正常细胞不存在。它们的表达通常与转移、不良预后，并降低总生存期。 Tn 抗原（N-乙酰半乳糖胺 O-连接至丝氨酸或苏氨酸）是 TACA 常见于癌症粘蛋白上。我们研究了 B 细胞对 Tn- 和其他物质反应的调节使用小鼠模型研究携带 TACA 的粘蛋白。我们的进展表明 TACA 的特异性，包括 Tn、在小鼠的先天 B (B1) 细胞群中高度富集。我们还发现 B 细胞固有的 PD-1 表达有效抑制肿瘤保护性 TACA 特异性抗体 (Ab) 反应，并且 CD4+ 细胞在 PD-1 抑制的情况下观察到的反应增加是必需的。最后，我们确定了一种 Tn 特异性 IgM 单克隆抗体，在体内具有显着且广泛的抗肿瘤活性。我们的理解调节抗体对 Tn 和其他 TACA 反应的机制非常有限。同样，我们的理解这些抗体有效杀死癌细胞的机制尚不完整。这些知识上的关键差距必须填充才能利用 TACA 反应性 B 细胞及其产生的抗体的保护能力。该提案的中心假设是，具有 TACA 天然特异性的 B 细胞在对癌症的有效抗肿瘤免疫反应。我们的主要目标是： 1) 确定机制 CD4+ T 细胞支持 TACA 特异性抗体反应的方式以及 PD-1 抑制改变的程度 Tn 特异性 B 细胞反应的多样性（目标 1），2) 确定 Tn 特异性 IgM 的机制促进肿瘤细胞杀伤和适应性抗肿瘤免疫反应（目标 2），以及 3) 检查人类 Tn 特异性 B 细胞库，并鉴定具有杀伤作用的广泛反应性 Tn 特异性抗体潜力（目标 3）。这些研究的结果预计将揭示新的机会：1) 利用具有癌症表达聚糖特异性的 B 细胞的抗肿瘤潜力，以及 2) 杠杆作用具有广泛反应性的 TACA 抗体，能够促进高度特异性的适应性和动态免疫反应靶向 TACA 相关肽。