Engaging immunosuppressive myeloid cells in the TME for the treatment of pancreatic cancer

摘要 尽管在过去的十年里，免疫疗法在肿瘤学上取得了巨大的成功，但很少有人做到这一点。 为胰腺癌患者提供了显著的益处。这个项目的长期目标是发展 胰腺癌临床治疗中有用的免疫疗法。总体目标 本申请的目的是(I)描述Marco在TME中的作用，(Ii)评估治疗效果 阻断这一受体的抗体，以及(Iii)通过一种 针对Marco和CD40的Fc增强抗体的组合。我们的中心假设是胰腺 癌症使肿瘤相关巨噬细胞重新极化为M2表型，这可以通过以下途径逆转 Marco与抗体结合，从而促进抗肿瘤反应。这个项目的基本原理是 确定表达MARCO的TAMS在胰腺癌中的免疫抑制作用将 可能为开发新的免疫疗法提供了强有力的科学框架。中环 假设将通过追求三个具体目标来验证：1)研制抗人癌症抗体 免疫疗法和建立大规模评估抗抗体的新检测方法，2)确定 Marco在胰腺癌TAMS极化中的作用，以及3)增强胰腺组织中的复极 使用Fc增强的CD40激动剂抗体2141-V11单独或与抗-TME联合应用的癌症TME HMARCO抗体..在第一个目标下，将产生针对人类Marco和 针对Fc受体结合进行了优化。在第二个目标中，通过基因工程使小鼠表达人类Marco 将研究它们在胰腺癌TME中的作用。以下是免疫细胞表达的特征 Marco认为可以通过抗体疗法进行靶向治疗，将对一组抗体变体进行测试，以确定 FC-体内最佳活性的要求。免疫球蛋白MARCO的表达及特性研究 微环境也将在人类胰腺癌标本中进行评估。最后，在第三个目标中，我们将 使用在AIMS 1和AIMS 2中获得的知识来测试针对胰腺肿瘤髓系轴的新组合。 在这里，将单独或联合检测Fc增强的抗CD40抗体的抗肿瘤活性。 胰腺癌模型中的抗Marco抗体。本申请中提出的研究具有创新性， 在研究人员看来，因为它专注于定义髓系细胞参与 免疫抑制的胰腺癌的TME，同时通过FC- 工程学。这项拟议的研究意义重大，因为它有望提供强有力的科学依据。 用于巨噬细胞靶向免疫疗法的开发。归根结底，这样的知识有可能 为将创新疗法转化为治疗胰腺癌提供了新的机会。

ABSTRACT Although the past decade was marked by the tremendous success of immunotherapeutics in oncology, few have provided significant benefit to patients with pancreatic cancer. The long-term goal of this project is to develop therapeutically useful immunotherapies for the clinical treatment of pancreatic cancer. The overall objectives in this application are to (i) characterize the role for MARCO in the TME, (ii) to evaluate the therapeutic efficacy of antibodies blocking this receptor, and (iii) improve antigen presentation within the pancreatic TME with a combination of Fc-enhanced antibodies targeting MARCO and CD40. Our central hypothesis is that pancreatic cancer repolarizes tumor associated macrophages to an M2 phenotype an this can be reversed through engagement of MARCO with antibodies, therefore promoting anti-tumor responses. The rationale for this project is that a determination of the immunosuppressive role of TAMs expressing MARCO in pancreatic cancer will likely offer a strong scientific framework whereby new immunotherapies can be developed. The central hypothesis will be tested by pursuing three specific aims: 1) Develop anti-human TAM antibodies for cancer immunotherapy and set up novel assays for large-scale evaluation of anti-TAM antibodies, 2) Define the role for MARCO in the polarization of TAMs in pancreatic cancer, and 3) Augment TAM repolarization in the pancreatic cancer TME using the Fc-enhanced CD40 agonist antibody 2141-V11, alone or in combination with anti- hMARCO antibodies.. Under the first aim, novel antibodies will be generated against human MARCO and optimized for Fc-receptor binding. In the second Aim, mice genetically engineered to express human MARCO will be studied for their role in the TME of pancreatic cancer. Following characterization immune cells expressing MARCO that can be targeted by antibody therapy, a panel of antibody variants will be tested to determine the Fc-requirements for optimal in vivo activity. MARCO expression and characterization of the immune microenvironment will also be evaluated in human pancreatic cancer specimens. Finally, in the third aim, we will use knowledge gained in Aims 1 and 2 to test novel combinations targeting the myeloid axis in pancreatic tumors. Here, the anti-tumor activity of the Fc-enhanced anti-CD40 antibody will be tested alone or in combination with anti-MARCO antibodies in pancreatic cancer models. The research proposed in this application is innovative, in the investigator’s opinion, because it focuses on defining novel pathways on myeloid cells contributing to the immune suppressive TME of pancreatic cancer, while identifying lead therapeutic candidates through Fc- engineering. The proposed research is significant because it is expected to provide strong scientific justification for the development of macrophage targeting immunotherapies. Ultimately, such knowledge has the potential of offering new opportunities for the translation of innovative therapies to the treatment of pancreatic cancer.