Modulating Immune Responses in Lung Cancer

调节肺癌的免疫反应

• 批准号: 8043323
• 负责人: SHERVEN SHARMA
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043323
• 关键词: Antibodies; Antitumor Response; Attenuated; Autologous; Biological Markers; CCL21 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL10 gene; CXCL9 gene; CXCR3 gene; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Development; Diagnosis; Diagnostic Neoplasm Staging; Effector Cell; Environment; Evaluation; Frequencies; Gene-Modified; Generations; Human; Immune; Immune response; Immunosuppression; Immunotherapy; Individual; Lead; Ligands; Lung; Lung Neoplasms; Lymphoid; Lytic; Malignant neoplasm of lung; Mediating; Modeling; Monitor; Mus; Myelogenous; Natural Killer Cells; Phenotype; Population; Pre-Clinical Model; Regulatory T-Lymphocyte; Research Priority; Role; Stromal Cells; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Therapy Clinical Trials; Treatment Efficacy; Tumor Burden; Tumor stage; United States; Veterans; base; chemokine; cytokine; immune activation; improved; in vivo; innovation; novel therapeutics; receptor; research study; response; subcutaneous; therapeutic target; tumor

DESCRIPTION (provided by applicant): Lung cancer is a major research priority for the Department of Veterans Affairs. In the United States and among our veteran population lung cancer remains the leading cause of cancer death. Despite the existing therapeutic efforts, the long term survival for lung cancer patients remains low, thus new therapeutic strategies are needed. In the proposed study we will evaluate an immune based therapy for lung cancer utilizing an orthotopic murine tumor model. We will determine the immune and innate effectors required in the generation of secondary lymphoid chemokine gene modified stromal cells (CCL21-SC) mediated antitumor activity and the role of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC) on the efficacy of CCL21-SC therapy. Our overall hypothesis is that CCL21-SC therapy will modulate antitumor responses in lung cancer. Hypothesis 1: Depleting CXCR3 and CCR7 receptor expressing effector cells [immune (CD4 T and CD8 T) and innate (NK and NKT)] will reduce CCL21-SC mediated antitumor activity. Hypothesis 2: Decreasing Treg and/or MDSC activity will improve the efficacy of CCL21-SC therapy. Specific Aims: Generation of antitumor effectors is a critical factor for successful immune based therapies. In aim 1, we will define the cellular requirements for the generation of CCL21-SC mediated antitumor responses in vivo by individually neutralizing CXCR3, CCR7, CD4, CD8, and NK cells with antibodies. The role of NKT cells will be defined utilizing the NKT deficient CD1d -/- mouse. The effect of specific effector cell neutralization on CCL21-SC therapy will be monitored by quantifying changes in: tumor burden, survival, the frequencies and functional activities of immune (CD4 T and CD8 T) and innate effector cells (NK and NKT). An understanding of the requisite effectors in the generation of CCL21-SC mediated antitumor responses will enable us to monitor similar cellular biomarkers in a lung cancer clinical trial of this therapy. Our preliminary findings indicate that the CCL21-SC therapy is very effective against tumor development in the subcutaneous (5-day) and orthotopic (7-day) Lewis Lung (3LL) tumor models. However, when therapy is initiated at a later stage of tumor development (subcutaneous 10-day or orthotopic 21-day), the efficacy of therapy is attenuated. The tumor uses strategies to counteract the immune responses that seek to destroy it. Tumor immune suppression can occur through the induction and recruitment of Treg and MDSC that block activation of immune and innate effectors. Whereas the frequency of Treg and MDSC is low in early stage tumor, they increase in later stage tumors. Thus, it is possible that Treg and/or MDSC are attenuating CCL21-SC therapy by reducing the activation and expansion of T lymphocytes and innate effector cells. In aim 2, to define the role of Treg or MDSC on the efficacy of CCL21-SC therapy, we will individually inactivate Treg or neutralize MDSC suppressor cell activity with antibodies. The impact of Treg inactivation or MDSC neutralization on the efficacy of CCL21-SC therapy will be monitored by quantifying changes in tumor burden and survival that will be correlated with changes in the frequencies and functional activities of immune and innate effectors. The impact of Treg inactivation or MDSC neutralization on CCL21-SC therapy will provide evidence for targeting of these suppressor phenotypes for enhancing CCL21-SC mediated antitumor activity. Findings from this study can lead to the development of innovative and effective immune therapies for lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death and among the Veteran population. With the existing therapeutic efforts, the long term survival for lung cancer patients remains low with only 15% surviving for 5 years following diagnosis. New therapeutic strategies are needed. Findings from this study have the potential for development of effective immune therapy for lung cancer.

描述（由申请人提供）： 肺癌是退伍军人事务部的主要研究优先事项。在美国和我们的资深人口中，肺癌仍然是癌症死亡的主要原因。尽管现有的治疗努力，但肺癌患者的长期生存仍然很低，因此仍需要新的治疗策略。 在拟议的研究中，我们将利用原位鼠肿瘤模型评估用于肺癌的免疫治疗。我们将确定生成继发性淋巴趋化因子基因改性基因细胞（CCL21-SC）介导的抗肿瘤活性以及调节性T细胞（TREG）和髓样抑制细胞（MDSC）对CCL21-SC治疗功效的作用的免疫和先天效应。我们的总体假设是CCL21-SC治疗将调节肺癌的抗肿瘤反应。假设1：耗尽CXCR3和CCR7受体表达效应细胞[免疫（CD4 T和CD8 T）以及先天（NK和NKT）]将降低CCL21-SC介导的抗肿瘤活性。假设2：降低Treg和/或MDSC活性将提高CCL21-SC治疗的功效。 具体目的：抗肿瘤效应子的产生是成功基于免疫疗法的关键因素。在AIM 1中，我们将通过单独中和带有抗体的CCL21-SC介导的抗肿瘤反应的细胞需求来体内产生CCL21-SC介导的抗肿瘤反应。使用NKT缺陷CD1D - / - 鼠标，将定义NKT细胞的作用。特异性效应细胞中和对CCL21-SC治疗的影响将通过量化：免疫（CD4 T和CD8 T）和先天效应细胞（NK和NKT）的肿瘤负担，生存，频率和功能活性的变化来监测。在这种疗法的肺癌临床试验中，了解CCL21-SC介导的抗肿瘤反应的必要效应子将使我们能够监测类似的细胞生物标志物。 我们的初步发现表明，CCL21-SC治疗非常有效地防止皮下（5天）和原位（7天）Lewis Lung（3LL）肿瘤模型的肿瘤发展。但是，当在肿瘤发育的后期开始治疗（皮下10天或原位21天）时，治疗的功效会减弱。肿瘤使用策略来抵消试图破坏其的免疫反应。肿瘤免疫抑制可以通过诱导和募集Treg和MDSC的诱导和募集，从而阻止免疫和先天效应子的激活。尽管Treg和MDSC在早期肿瘤中的频率很低，但它们在后期肿瘤中增加。因此，TREG和/或MDSC可能通过减少T淋巴细胞和先天效应细胞的激活和扩展来减轻CCL21-SC治疗。 在AIM 2中，为了定义Treg或MDSC对CCL21-SC治疗功效的作用，我们将单独失活或中和用抗体中和MDSC抑制细胞活性。 Treg失活或MDSC中和对CCL21-SC治疗功效的影响将通过量化肿瘤负担的变化和生存的变化来监测，这将与免疫和先天效应子的频率和功能活性的变化相关。 Treg灭活或MDSC中和对CCL21-SC治疗的影响将为这些抑制作用表型提供证据，以增强CCL21-SC介导的抗肿瘤活性。 这项研究的结果可能导致开发用于肺癌的创新和有效的免疫疗法。 公共卫生相关性： 肺癌是癌症死亡和退伍军人口中的主要原因。通过现有的治疗工作，肺癌患者的长期生存率仍然很低，诊断后仅15％存活了5年。需要新的治疗策略。这项研究的结果有可能开发有效的肺癌免疫治疗。