Characterization of the interaction between inflammation and cancer progression

本项目的目标是研究细胞和分子机制， 所述细胞因子在体内调节炎症和宿主抗肿瘤免疫应答， 特别是当它们涉及肿瘤和器官之间复杂的细胞相互作用时 微环境我们的第一种方法是描述肿瘤浸润的特征。 白细胞在肿瘤进展过程中。使用可移植的转移性肾细胞癌， 我们正在分析在肾脏中发展的原发性肿瘤中包含的白细胞， 以及肺和肝脏中的肿瘤，这是肿瘤的原发和继发部位 转移，分别。趋化因子是趋化性细胞因子，其用于募集特异性 白细胞亚群进入正在进行的炎症反应的区域。我们利用老鼠 缺乏各种趋化因子受体，以确定单核细胞，T细胞 并且其它炎性细胞被募集到肿瘤部位。一旦出现在发展中国家， 在肿瘤部位，这些细胞能够产生许多不同的可溶性介质，例如 干扰素γ（IFN）、一氧化氮和VEGF可能影响肿瘤 进展通过调节这些细胞类型在肿瘤内积累的能力，我们 确定这些细胞在原发性肿瘤进展和 转移到远处器官。我们的免疫治疗方案包括IL-2或IL-15， 与CD 40的激动性抗体组合。在用这种药物治疗荷瘤小鼠后， 结合，我们已经确定了巨噬细胞和T细胞的招募，似乎是 抗肿瘤反应的关键介质。我们的数据表明， 单独抗CD 40与其单独抗CD 40介导的生物学效应的显著机制差异 与IL-2联合使用，包括协同上调IFNγ 和控制肿瘤负荷的一氧化氮表达。在另一种方法中，我们已经开始 分析树突状细胞在抗肿瘤反应中的作用， 免疫疗法IL-12是一种有效的免疫调节细胞因子， 抗肿瘤作用本身，增加树突状细胞在肝脏不同， 淋巴器官如脾脏。我们目前正在分析， 联合收割机将IL-12与其他免疫调节细胞因子如IL-2或IL-15结合， 通过增强抗原提呈的抗肾细胞癌的有效免疫应答 这些重要的效应细胞的能力。此外，在与信号之间存在动态串扰。 树突状细胞和NK和NK-T细胞以及调节树突状细胞和NK和NK-T细胞的数量或功能的疗法。 这些细胞可能对DC引发T细胞特异性免疫应答的能力具有显著影响。 抗肿瘤反应。此外，我们已经确定了一个特定的积累的T调节 肿瘤微环境中的细胞，这可能有助于抑制抗肿瘤反应。我们 已经确定了肿瘤坏死因子α（TNF α），一种关键的促炎因子， 细胞因子，因为可能参与T调节细胞的募集和/或扩增。 细胞我们正在通过分子和生物化学方法靶向这种细胞因子， 最终在临床上可用于抵消抑制性肿瘤的形成 微环境我们还确定了NK-T细胞的假定免疫抑制作用， 我们现在正在开发免疫疗法， 不同器官的细胞。通过表征炎症在肿瘤进展中的作用， 这些重叠的方法将有望导致免疫系统的发展， 使炎症反应偏向于对抗肿瘤生长的方法。

The goal of this project is to investigate the cellular and molecular mechanisms by which cytokines regulate inflammation and host anti-tumor immune responses in vivo, particularly as they relate to the complex cellular interactions between the tumor and organ microenvironments. Our first approach is to characterize the profile of tumor-infiltrating leukocytes during tumor progression. Using a transplantable, metastatic renal cell carcinoma, we are analyzing leukocytes contained within the primary tumors that develop in the kidney as well as those in the lung and livers, which serve as primary and secondary sites of tumor metastases, respectively. Chemokines are chemotactic cytokines that serve to recruit specific leukocyte subsets into regions of ongoing inflammatory responses. We are utilizing mice deficient in various chemokine receptors to identify the mechanisms whereby monocytes, T cells and other inflammatory cells are recruited to the tumor site. Once present at the developing tumor site, these cells are capable of producing many different soluble mediators, such as interferon gamma (IFNγ), nitric oxide, and VEGF that may influence tumor progression. By regulating the ability of these cell types to accumulate within tumors, we are identifying the role that these cells play during both primary tumor progression and metastasis to distant organs. Our immunotherapeutic regimens include IL-2 or IL-15 in combination with agonistic antibody to CD40. After treating tumor-bearing mice with this combination, we have identified the recruitment of macrophages and T cells that appear to be critical mediators of anti-tumor responses. Our data have illustrated the potential for dramatic mechanistic differences in biological effects mediated by anti-CD40 alone versus its use in combination with IL-2 that includes the synergistic upregulation of IFNγ and nitric oxide expression that controls tumor burden. In another approach, we have begun to analyze the role that dendritic cells play during the anti-tumor responses achieved by immunotherapies. Treatment with IL-12, a potent immunoregulatory cytokine with dramatic anti-tumor effects on its own, increases dendritic cells differently in the liver as compared to lymphoid organs such as the spleen. We are currently analyzing whether therapies that combine IL-12 with other immunomodulatory cytokines such as IL-2 or IL-15 offer a more effective immune response against renal cell carcinoma by enhancing the antigen presenting capability of these important effector cells. Furthermore, there is dynamic cross-talk between dendritic cells and NK and NK-T cells and therapies that modulate the numbers or function of these cells may have significant impact upon the ability of DC to prime T cells for specific anti-tumor responses. In addition, we have identified a specific accumulation of T regulatory cells within the tumor microenvironment, which may serve to suppress anti-tumor responses. We have identified tumor necrosis factor alpha (TNFalpha), a critical proinflammatory cytokine, as possibly being involved in the recruitment and/or expansion of T regulatory cells. We are targeting this cytokine by molecular and biochemical approaches that may ultimately be useful in the clinic for counteracting the establishment of a suppressive tumor microenvironment. We have also identified a putative immunosuppressive role for NK-T cells and we are now developing immunotherapeutic regimens that reduce the numbers and activity of these cells in different organs. By characterizing the role of inflammation upon tumor progression, these overlapping approaches will hopefully lead to the development of immunotherapeutic approaches that skew the inflammatory response to counter tumor growth.