Spontaneous humoral responses open opportunities for novel immunotherapies against human cancer

项目总结/摘要 B细胞介导的体液应答与多种癌症中的免疫保护相关。细胞适应性 免疫力与体液反应协调发展，以达到最大的有效性和长期 记忆在这个项目中，我们将研究肿瘤衍生抗体的自发影响，以及 通过两种不同的新型抗肿瘤免疫机制发挥其免疫潜力。一是 假设具有转胞吞能力的伊加抗体可以靶向细胞内抗原。第二、 天然产生的抗PD-1抗体有助于支持T细胞自发施加的免疫压力， 和B细胞对抗恶性进展，但削弱免疫检查点阻断治疗的有效性 （ICB）。这两种假设都是基于我们对肿瘤源性伊加胞内体转胞质作用的初步发现 通过与人卵巢癌细胞中的多聚免疫球蛋白受体（pIgR）结合，表明 使用伊加可以靶向细胞内的致癌驱动因子，并自发产生PD-1特异性伊加和IgG 抗体在人类卵巢癌床上。二聚体伊加被内化并通过胞质转运 卵巢癌细胞与pIgR相互作用后。考虑到伊加靶向细胞内病毒抗原的能力， 在核内体区室，我们将利用我们对KRASG 12 D突变特异性的二聚伊加抗体来跟踪 它的内化和与突变型与野生型（WT）KRAS的相互作用，以及它的亚细胞定位 和治疗潜力。我们预测细胞内致癌驱动因子的突变依赖于核内体 再循环（即，KRAS）可以用抗原特异性二聚体伊加有效靶向。通过定义功效和 在人源化动物模型中用伊加中和细胞内突变的KRAS的特异性，我们可以铺平 新的免疫疗法有效地针对基本的，但不可治愈的机制的方式。另 另一方面，通过定义自发产生的抗PD-1循环抗体的频率和功能相关性， 卵巢癌患者的自身抗体，我们将确定这些自身抗体的预后相关性。 此外，我们的概念是自发产生的抗PD-1抗体有助于支持免疫应答。 T和B细胞自发施加的压力对抗癌症进展，但损害IC B的有效性 这将对开发个性化的免疫干预措施产生明显的影响， 最大限度地提高对患者的治疗效果。总之，我们将提供一个基础，为小说量身定制 卵巢癌的免疫疗法，基于对其独特免疫生物学的更好理解， 将临床样品与相关的临床前肿瘤模型相结合。

PROJECT SUMMARY/ABSTRACT B cell-mediated humoral responses are associated with immune protection in multiple cancers. Cellular adaptive immunity progresses in coordination with humoral responses to achieve maximum effectiveness and long-term memory. In this project, we will investigate the spontaneous influence of tumor-derived antibodies, as well as their immunotherapeutic potential, through two different and novel mechanisms of anti-tumor immunity. First, we hypothesized that IgA antibodies with the transcytosis capacity could target intracellular antigens. Second, naturally produced anti-PD-1 antibodies contribute to support the immune pressure spontaneously exerted by T and B cells against malignant progression but impair the effectiveness of immune-checkpoint-blockade therapy (ICB). Both the hypothesis is based on our preliminary findings of tumor-derived IgA transcytoses in endosomes through binding with polymeric immunoglobulin receptor (pIgR) in human ovarian cancer cells, suggesting that intracellular oncodrivers could be targeted using IgA, and spontaneously produced PD-1-specific IgA and IgG antibodies in human ovarian cancer bed. Dimeric IgA gets internalized and transcytoses all the way through ovarian cancer cells upon interaction with pIgR. Considering the ability of IgA to target intracellular viral antigens at endosomal compartments, we will utilize our dimeric IgA antibodies specific for the KRASG12D mutation to track its internalization and interaction with mutated vs. wild-type (WT) KRAS, as well as its subcellular localization and therapeutic potential. We predict that mutations in intracellular oncodrivers dependent on endosomal recycling (i.e., KRAS) could be effectively targeted with antigen-specific dimeric IgA. By defining the efficacy and specificity of neutralizing intracellular mutated KRAS with IgA in humanized animal models, we could pave the way for novel immunotherapies effectively targeting essential and yet undruggable mechanisms. On the other hand, by defining the frequency and functional relevance of spontaneously generated anti-PD-1 circulating antibodies in ovarian cancer patients, we will determine the prognostic relevance of these auto-antibodies. Further, our concept is that spontaneously produced anti-PD-1 antibodies contribute to support the immune pressure spontaneously exerted by T and B cells against cancer progression but impair the effectiveness of ICB therapy, which will have obvious implications for developing personalized immunotherapeutic interventions to maximize effectiveness in the right set of patients. In summary, we will offer a basis for novel tailored immunotherapies against ovarian cancer, based on a better understanding of its unique immunobiology, by combining clinical samples with relevant preclinical tumor models.