Spontaneous humoral responses open opportunities for novel immunotherapies against human cancer

项目摘要/摘要 在多种癌症中，B细胞介导的体液反应与免疫保护有关。细胞自适应 免疫与体液反应协调发展，以实现最大效力和长期 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 它们的免疫治疗潜力，通过两种不同的和新的抗肿瘤免疫机制。首先，我们 假设具有跨细胞吞噬能力的IgA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)。这两种假说都是基于我们对内体中肿瘤来源的IgA转胞体的初步发现。 通过与人卵巢癌细胞中的聚合免疫球蛋白受体(PIgR)结合，提示 细胞内的癌驱动因素可以用IgA作为靶点，并自发地产生PD-1特异性的IgA和Ig G 人卵巢癌床中的抗体。二聚体免疫球蛋白A被内化并一直跨细胞 卵巢癌细胞与pIgR相互作用。考虑到IgA靶向细胞内病毒抗原的能力 在内体隔室，我们将利用我们针对KrasG12D突变的二聚体IgA抗体来追踪 它与突变型与野生型(WT)KRAS的内化和相互作用及其亚细胞定位 和治疗潜力。我们预测细胞内致癌基因突变依赖于内噬菌体 抗原特异性二聚体IgA可以有效地靶向循环(即KRAS)。通过定义疗效和 在人源化动物模型中，用IgA中和细胞内突变的KRAS的特异性，为进一步研究 有效地针对基本但不可用药的机制的新型免疫疗法的方法。另一方面 另一方面，通过定义自发产生的抗PD-1循环的频率和功能相关性 在卵巢癌患者中，我们将确定这些自身抗体与预后的相关性。 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 T和B细胞自发施加压力阻止肿瘤进展但削弱ICB的效果 治疗，这将对开发个性化的免疫治疗干预措施具有明显的影响 在正确的患者组中最大限度地提高有效性。总之，我们将为小说量身定做提供一个基础 基于对卵巢癌独特免疫生物学的更好了解，针对卵巢癌的免疫疗法，通过 结合临床标本和相关的临床前肿瘤模型。

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.