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

摘要 肿瘤相关糖类抗原(TACA)是一种异常糖基化产物，表达于 癌细胞，但在大多数正常细胞上不存在。它们的表达通常与转移有关，很差 预后，并降低总存活率。TN抗原(N-乙酰半乳糖胺O-连接到丝氨酸或苏氨酸)是 通常在癌症粘液中发现的一种TACA。我们已经研究了B细胞对TN-和其他的反应的调节 使用小鼠模型携带塔卡粘蛋白。我们的进展表明，包括TN在内的TACA的特殊性， 在小鼠的先天B(B1)细胞群中高度丰富。我们还发现B细胞固有的PD-1 表达可有效抑制肿瘤保护性TACA特异性抗体(Ab)反应和CD4+细胞 在PD-1抑制的背景下观察到的增加的反应是必需的。最后，我们确定了 一种在体内具有显著和广泛抗肿瘤活性的TN特异性IgM单抗。我们对此的理解 调节抗体对TN和其他TACA的反应的机制非常有限。同样，我们对 这些抗体有效杀死癌细胞的机制尚不完整。这些知识中的关键差距 必须填充，以利用TACA反应性B细胞及其产生的抗体的保护能力。 这一建议的中心假设是，具有TACA天然特异性的B细胞在 对癌症有效的抗肿瘤免疫反应。我们的主要目标是：1)确定机制 CD4+T细胞通过何种方式支持TACA特异性抗体应答以及PD-1抑制在多大程度上改变 TN特异性B细胞反应的多样性(目标1)，2)确定TN特异性IgM 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细胞谱系及广谱TN特异性抗肿瘤抗体 潜力(目标3)。这些研究的发现有望为1)提供新的机会 利用B细胞对癌症表达的多糖的特异性来利用其抗肿瘤的潜力和2)杠杆作用 广谱反应性TACA单抗促进高度特异的适应性和动态免疫反应 靶向TACA相关多肽。

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.