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

• 批准号: 10502322
• 负责人: Karen M Haas
• 金额: $ 41.98万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10502322
• 关键词: Acetylgalactosamine; Adjuvant; Adoptive Cell Transfers; Antibodies; Antibody Response; Antigens; Antitumor Response; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Blood Circulation; CD4 Positive T Lymphocytes; Carbohydrates; Cell Communication; Cells; Complement; Complement Inactivators; Data; Development; Flow Cytometry; Fostering; Galactosamine; Goals; Human; Immune response; Immunoglobulin M; Knowledge; Lead; 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-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

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 肿瘤相关的碳水化合物抗原（TACAS）是异常的糖基化产物，在 癌细胞，但大多数正常细胞不存在。它们的表达通常与转移有关，差 预后和总体生存率降低。 TN抗原（​​N-乙酰乳糖胺O-Linch与丝氨酸或苏氨酸的链接）是 经常在癌症上发现的TACA。我们已经调查了B细胞对TN-和其他的B细胞反应的调节 使用小鼠模型的含Taca粘蛋白。我们的进度表明，包括TACA的特异性，包括TN 在小鼠的先天B（B1）细胞种群中高度富集。我们还发现B细胞中心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抑制作用中观察到的响应增加所必需。最后，我们确定了 TN特异性IgM单克隆AB，在体内具有显着且较大的抗肿瘤活性。我们对 调节AB对TN和其他TACA的反应的机制非常有限。同样，我们对 这些腹肌有效杀死癌细胞的机制不完整。这些知识的关键差距 必须填充以利用Taca反应B细胞的保护能力及其产生的ABS的保护能力。 该提议的核心假设是，具有自然特异性塔卡斯的B细胞在 有效的抗肿瘤免疫反应对癌症。我们的主要目标是：1）确定机制 CD4+ T细胞支持TACA特异性AB反应以及PD-1抑制的程度 TN特异性B细胞反应的多样性（AIM 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（AIM 2），3）检查 人类中TN特异性B细胞的曲目，并鉴定出广泛反应性的TN特异性ABS肿瘤 潜力（目标3）。预计这些研究的发现将揭示新的机会到1） 利用B细胞具有特异性的B细胞的抗肿瘤潜力，2）杠杆作用 广泛反应性TACA ABS的能力促进高度特异性适应性和动态免疫反应 靶向TACA相关的肽。