Host's Genes that Control Lymphocyte Infiltration of Tumors

控制肿瘤淋巴细胞浸润的宿主基因

• 批准号: 7464350
• 负责人: PETER DEMANT
• 金额: $ 29.45万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-05 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464350
• 关键词: Adhesions; Affect; Alleles; Animals; Biological Assay; Biological Process; Blood Vessels; Bone Marrow; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Prognosis; Cancer Vaccines; Candidate Disease Gene; Carcinogens; Cell Adhesion Molecules; Cells; Characteristics; Chimera organism; Clinical Research; Colorectal; Congenic Mice; Congenic Strain; DNA analysis; Data; Distal; Effector Cell; Exercise; Exhibits; Experimental Models; Failure; Frequencies; Gene Structure; Generations; Genes; Genetic; Genetic Polymorphism; Genome; Genomic Segment; Germ Lines; Goals; Heterogeneity; Homologous Gene; Human; Immune; Immune system; Immunotherapy; In Vitro; Individual; Infection; Infiltration; International Union Against Cancer; Invaded; Lead; Light; Lung Neoplasms; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Matrix Metalloproteinases; Measures; Mediating; Molecular; Mus; Neoplasm Metastasis; Normal tissue morphology; Numbers; Outcome; Patient Selection; Patients; Probability; Process; Prognostic Marker; Public Health; Purpose; Regulation; Regulatory T-Lymphocyte; Role; Solid Neoplasm; Staging; Standards of Weights and Measures; T-Cell Receptor; T-Lymphocyte; TNM; Testing; Time; Tissues; Transgenic Mice; Tumor Antigens; Tumor Cell Invasion; Tumor Tissue; Validation; Variant; base; chemokine; congenic; gene function; granulocyte; improved; insight; interest; killings; macrophage; melanoma; migration; neoplastic cell; novel strategies; novel therapeutics; outcome forecast; positional cloning; prevent; prognostic; response; size; therapeutic target; trafficking; tumor; tumor growth; tumorigenesis; vaccine effectiveness

DESCRIPTION (provided by applicant): Capacity of lymphocytes to infiltrate tumors is essential for T-lymphocyte-mediated tumor destruction. In human cancer a high degree of tumor infiltration is associated with a better prognosis. In fact, the degree of infiltration is an even better prognostic predictor than the standard TNM UICC stage. Tumors undergoing immunotherapy often escape destruction even in the systemic presence of large numbers of tumor-specific effector cells, because the immune cells do not reach the tumor. However, neither the clinical studies on relationship between lymphocyte infiltration and prognosis, nor the studies on effects of immunotherapy explain why some patients have a high and others low degree of infiltration. A prediction of the capacity of lymphocytes to infiltrate tumors would be important for assessment of cancer prognosis and for selection of patients who will likely respond to immunotherapy. However, in spite of extensive definition of sequential processes and molecules that contribute to adhesion of lymphocytes to the vascular wall, diapedesis, and invasion of tumors, the prediction of the outcome of this process in individual patients is not yet possible. We have identified a novel approach to assessment of individual propensity for tumor infiltration. We show that propensity for tumor infiltration by lymphocytes is genetically controlled by the genome of the host (patient) and hence it can be assessed by analysis of DNA of any normal tissue, without analyzing tumor tissues. This hypothesis is based on the unexpected finding that in the mouse the presence and intensity of tumor infiltration is controlled genetically. We mapped four such genetic loci, Lynf1 - Lynf4 (Lynf = Lymphocyte infiltration). These loci do not encode any of the > 50 genes (adhesion molecules, chemokines, matrix metalloproteinases etc.) that have been previously inferred to participate in lymphocyte trafficking and tumor infiltration. Therefore the Lynf genes likely represent a new group of factors participating in these processes. Their analysis will offer new insights into interactions of tumors with immune system and they may become new therapeutic targets. It would also help to avoid immunotherapy in patients with low propensity for tumor infiltration and lead to an individualized choice of other treatments instead. To study the function of these genes and identify them molecularly, we will generate congenic lines carrying these genes in short chromosomal segments (less than 2-4 cM) so that their functions can be analyzed with little interference from other genes. We shall determine whether these genes influence tumor growth, determine selectively infiltration by certain lymphocyte subclasses, and whether they operate systemically in bone marrow derived cells or locally in the tumor and its microenvironment. We will identify at least one Lynf gene molecularly, so its function can be studied also in humans. PUBLIC HEALTH RELEVANCE: All animals and humans contain cells, lymphocytes that are responsible for defense against infections and cancer. However, for unknown reasons in many patients these cells are not present in sufficient numbers inside the cancer tissue, which can increase probability of invasion and metastasis, shorten survival time, and lower effectiveness of vaccines against cancer. We discovered that in the mouse are genes that determine whether the lymphocytes will invade cancer on not, and will study the function and structure of these genes, in order to be able to apply this discovery in to improved treatment of human cancers.

描述（由申请人提供）：淋巴细胞浸润肿瘤的能力对于 T 淋巴细胞介导的肿瘤破坏至关重要。在人类癌症中，高度的肿瘤浸润与更好的预后相关。事实上，浸润程度是比标准 TNM UICC 分期更好的预后预测指标。即使全身存在大量肿瘤特异性效应细胞，接受免疫治疗的肿瘤也常常逃脱破坏，因为免疫细胞无法到达肿瘤。然而，无论是淋巴细胞浸润与预后关系的临床研究，还是免疫治疗效果的研究，都无法解释为什么有的患者浸润程度高，有的患者浸润程度低。预测淋巴细胞浸润肿瘤的能力对于评估癌症预后和选择可能对免疫治疗有反应的患者非常重要。然而，尽管对淋巴细胞粘附到血管壁、血细胞渗出和肿瘤侵袭的顺序过程和分子有广泛的定义，但预测个体患者中这一过程的结果尚不可能。我们已经确定了一种评估个体肿瘤浸润倾向的新方法。我们表明，淋巴细胞浸润肿瘤的倾向是由宿主（患者）的基因组遗传控制的，因此可以通过分析任何正常组织的 DNA 来评估，而无需分析肿瘤组织。这一假设是基于一个意外的发现，即在小鼠中，肿瘤浸润的存在和强度是受基因控制的。我们绘制了四个这样的基因位点：Lynf1 - Lynf4（Lynf = 淋巴细胞浸润）。这些基因座不编码先前推断参与淋巴细胞运输和肿瘤浸润的超过 50 个基因（粘附分子、趋化因子、基质金属蛋白酶等）中的任何一个。因此，Lynf 基因可能代表参与这些过程的一组新因素。他们的分析将为肿瘤与免疫系统的相互作用提供新的见解，并且它们可能成为新的治疗靶点。它还将有助于避免肿瘤浸润倾向低的患者接受免疫治疗，并导致个体化选择其他治疗方法。为了研究这些基因的功能并对其进行分子鉴定，我们将生成在短染色体片段（小于2-4 cM）中携带这些基因的同源系，以便可以在很少受到其他基因干扰的情况下分析它们的功能。我们将确定这些基因是否影响肿瘤生长，确定某些淋巴细胞亚类的选择性浸润，以及它们是否在骨髓来源的细胞中系统地发挥作用，或者在肿瘤及其微环境中局部发挥作用。我们将从分子角度鉴定至少一个 Lynf 基因，因此也可以在人类中研究其功能。 公共卫生相关性：所有动物和人类都含有负责防御感染和癌症的细胞、淋巴细胞。然而，由于未知的原因，在许多患者中，这些细胞在癌症组织内的数量不足，这会增加侵袭和转移的可能性，缩短生存时间，并降低癌症疫苗的有效性。我们在小鼠体内发现了决定淋巴细胞是否会侵入癌症的基因，并将研究这些基因的功能和结构，以便能够将这一发现应用于改进人类癌症的治疗。