Characterization of the interaction between inflammation and cancer progression

炎症与癌症进展之间相互作用的表征

• 批准号: 8349226
• 负责人: Robert Wiltrout
• 金额: $ 41.93万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349226
• 关键词: Antibodies; Antigen-Presenting Cells; Antigens; Antitumor Response; Biochemical; Biological; CD8B1 gene; Cell Therapy; Cell physiology; Cells; Clinic; Clinical; Clinical Trials; Complex; Data; Dendritic Cells; Development; Distant; Effector Cell; Equilibrium; Event; Future; Goals; Human; IL2 gene; Immune; Immune response; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-12; Interleukin-15; Interleukin-2; Kidney; Lead; Leukocytes; Liver; Lung; Lymphoid; Mediating; Mediator of activation protein; Metastatic Renal Cell Cancer; Modeling; Molecular; Mus; Myelogenous; Neoplasm Metastasis; Nitric Oxide; Organ; Pharmaceutical Preparations; Play; Primary Neoplasm; Publishing; Recruitment Activity; Regimen; Regulation; Regulatory T-Lymphocyte; Renal Cell Carcinoma; Role; Site; Spleen; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; TNFRSF5 gene; Therapeutic; Translating; Tumor Antigens; Tumor Burden; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Endothelial Growth Factors; base; carcinogenesis; cell type; chemokine; chemokine receptor; clinical efficacy; cytokine; human FRAP1 protein; immunoregulation; in vivo; killings; mTOR inhibition; macrophage; monocyte; pre-clinical; response; tumor; tumor growth; tumor progression

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 (IFNg), 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 IFNg and nitric oxide expression that controls tumor burden. To date, we have shown IL-2/aCD40 induces enhanced antitumor responses that depend on the infiltration of established tumors by effector CD8+ T cells and a concomitant IFNg-dependent reduction in CD4+/FoxP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC) and Th2 chemokine expression within the tumor-microenvironment. These results may help to explain the limited clinical efficacy of aCD40 as a single agent based on its inability to remove Tregs and MDSC specifically from within the tumor microenvironment and they suggest that anti-CD40 may be more beneficial in combination with other selected immune agents, such as IL-2. We have also translated our earlier preclinical findings using IL2 in combination with IL12 to human clinical trials. Our current and future studies seek to clarify the cellular and molecular events critical for the observed biological effects of aCD40, and the potential for complementary use of aCD40 with rationally selected molecularly targeted agents. In another approach, we have combined anti-CD40 with an ATP competitive mTOR drug, AZD8055, developed by AstraZeneca. The rationale for this strategy is two-fold. First, mTOR inhibition represents is currently a leading clinical target for RCC. We also hypothesized that combining AZD8055 with aCD40 antibody would induce more efficient antitumor effects by a combination of direct tumor killing and subsequent release of tumor-associated antigens to antigen presenting cells and coincident modulation of immune cell functions in vivo. The results of our recently published study show that in a syngeneic mouse metastatic renal cell carcinoma (RCC) model, AZD8055 and aCD40 synergize for tumor regression by activating macrophages and DCs and inducing strong Th1 immune responses in the tumor microenvironment. 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 (TNFa), 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.

该项目的目标是研究细胞因子在体内调节炎症和宿主抗肿瘤免疫反应的细胞和分子机制，特别是当它们涉及肿瘤和器官微环境之间复杂的细胞相互作用时。我们的第一种方法是描述肿瘤进展过程中肿瘤浸润性白细胞的特征。使用可移植的转移性肾细胞癌，我们分析了在肾脏以及肺和肝脏中发展的原发性肿瘤中所含的白细胞，这些肿瘤分别作为肿瘤转移的原发性和继发性部位。趋化因子是趋化性细胞因子，其用于将特定的白细胞亚群募集到正在进行的炎症反应的区域中。我们正在利用各种趋化因子受体缺陷的小鼠来鉴定单核细胞、T细胞和其他炎性细胞被募集到肿瘤部位的机制。一旦出现在发展中的肿瘤部位，这些细胞能够产生许多不同的可溶性介质，如干扰素γ（IFNg）、一氧化氮和VEGF，其可能影响肿瘤进展。通过调节这些细胞类型在肿瘤内积累的能力，我们正在确定这些细胞在原发性肿瘤进展和转移到远处器官过程中所起的作用。我们的免疫治疗方案包括IL-2或IL-15与CD 40的激动性抗体的组合。在用这种组合治疗荷瘤小鼠后，我们已经确定了巨噬细胞和T细胞的募集，它们似乎是抗肿瘤反应的关键介质。我们的数据已经说明了单独抗CD 40与其与IL-2联合使用介导的生物学效应的显著机制差异的可能性，包括IFNg和一氧化氮表达的协同上调，其控制肿瘤负荷。迄今为止，我们已经显示IL-2/aCD 40诱导增强的抗肿瘤应答，其依赖于效应CD 8 + T细胞对已建立的肿瘤的浸润，以及伴随的CD 4 +/FoxP 3+调节性T细胞（T细胞）、髓源性抑制细胞（MDSC）和肿瘤微环境内Th 2趋化因子表达的IFN-γ依赖性降低。这些结果可能有助于解释aCD 40作为单一药物的有限临床疗效，这是基于其不能从肿瘤微环境中特异性地去除TcB和MDSC，并且它们表明抗CD 40与其他选定的免疫剂（例如IL-2）组合可能更有益。我们还将我们早期使用IL 2与IL 12组合的临床前发现转化为人类临床试验。我们目前和未来的研究旨在阐明对观察到的aCD 40生物学效应至关重要的细胞和分子事件，以及aCD 40与合理选择的分子靶向药物互补使用的潜力。在另一种方法中，我们将抗CD 40与阿斯利康开发的ATP竞争性mTOR药物AZD 8055相结合。这一战略的理由有两方面。首先，mTOR抑制是目前RCC的主要临床靶点。我们还假设，AZD 8055与aCD 40抗体的组合将通过直接肿瘤杀伤和随后向抗原呈递细胞释放肿瘤相关抗原以及体内免疫细胞功能的同步调节的组合诱导更有效的抗肿瘤作用。我们最近发表的研究结果表明，在同基因小鼠转移性肾细胞癌（RCC）模型中，AZD 8055和aCD 40通过激活巨噬细胞和DC并在肿瘤微环境中诱导强烈的Th 1免疫应答，协同肿瘤消退。在另一种方法中，我们已经开始分析树突状细胞在免疫疗法实现的抗肿瘤反应中所起的作用。与淋巴器官如脾相比，用IL-12（一种自身具有显著抗肿瘤作用的强效免疫调节细胞因子）治疗以不同方式增加肝脏中的树突状细胞。我们目前正在分析联合收割机IL-12与其他免疫调节细胞因子（如IL-2或IL-15）联合治疗是否能通过增强这些重要效应细胞的抗原呈递能力，提供更有效的抗肾细胞癌免疫应答。此外，树突细胞与NK和NK-T细胞之间存在动态串扰，并且调节这些细胞的数量或功能的疗法可能对DC引发T细胞进行特异性抗肿瘤应答的能力具有显著影响。此外，我们已经确定了肿瘤微环境中T调节细胞的特异性积累，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），一种重要的促炎细胞因子，可能参与募集和/或扩增的T调节细胞。我们正在通过分子和生物化学方法靶向这种细胞因子，这些方法最终可能在临床上用于抵消抑制性肿瘤微环境的建立。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抑制方案，以减少这些细胞在不同器官中的数量和活性。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方法的发展，这些免疫方法使炎症反应偏离以对抗肿瘤生长。