Immunobiology and immunotherapy of pancreatic cancer

描述（由申请人提供）：免疫系统对肿瘤生长有积极或消极的影响，这一观点已被广泛接受。在许多情况下，肿瘤产生免疫抑制微环境，有助于肿瘤逃避免疫破坏，特别是在胰腺导管腺癌（PDA）中。我们之前已经证明CD40激动剂可以改变肿瘤微环境，并在人类和基因工程小鼠中触发巨噬细胞依赖性的PDA破坏。此外，使用一种新的遗传谱系追踪方法，我们现在有了初步的数据，表明侵袭性行为和转移级联的其他因素发生在疾病的早期阶段，并受到炎症的关键调节。因此，我们假设针对PDA的免疫抑制机制将为这种治疗抵抗性疾病提供新的治疗方法。特别是，我们假设CD40激活可以重新教育巨噬细胞和T细胞，从而触发原发性PDA肿瘤的消退，并与免疫系统的其他元素协同阻止转移性扩散。我们的最终目标是基于对肿瘤微环境中免疫调节网络的理解，设计新的PDA治疗方法。该建议使用多pi机制，并将小鼠模型和人类患者纳入其中。具体目的是：(1)了解激动剂CD40 mAb抗肿瘤作用的免疫学机制；(2)了解炎症和CD40激活如何影响转移级联；(3)在可切除胰腺癌患者的临床试验中确定CD40 mAb的临床和免疫学影响。

DESCRIPTION (provided by applicant): It is widely accepted that the immune system can exert either positive or negative influences on tumor growth. In many instances, tumors create an immunosuppressive microenvironment which contributes to tumor escape from immune destruction, particularly in pancreatic ductal adenocarcinoma (PDA). We have previously demonstrated that CD40 agonists can alter the tumor microenvironment and trigger a macrophage-dependent destruction of PDA in both humans and genetically engineered mice. Moreover, using a novel genetic lineage-tracing methodology, we now have preliminary data that invasive behavior and other elements of the metastatic cascade occur at the earliest stages of disease and are critically regulated by inflammation. Thus, we hypothesize that targeting immunosuppressive mechanisms in PDA will provide novel approaches to therapy for this otherwise treatment-resistant disease. In particular, we hypothesize that CD40 activation can re-educate both macrophages and T cells to trigger regression of a primary PDA tumor and impede metastatic spread in concert with other elements of the immune system. Our ultimate goal is to devise new therapies for PDA based on an understanding of immune regulatory networks in the tumor microenvironment. This proposal uses the multi-PI mechanism and will incorporate both mouse models and human patients. Specific Aims are to: (1) Understand the immunological mechanism(s) underlying the anti-tumor effect of agonist CD40 mAb, (2) Understand how inflammation and CD40 activation influence the metastatic cascade, 3) Determine the clinical and immunological impact of CD40 mAb in a clinical trial of patients with resectable pancreatic carcinoma. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma (PDA) carries the poorest prognosis of any major cancer, and thus innovative new approaches to therapy are desperately needed. In this proposal, we seek to "reprogram" specific cells in the immune system, converting them from bystanders to tumor-cell killers (e.g. by CD40 activation). These studies will incorporate mouse models and human patients and thus set the stage for developing therapies for this treatment-refractory disease.