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: 8015290
• 负责人: PETER DEMANT
• 金额: $ 30.25万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015290
• 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 Cancer; 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; IL2RA gene; 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; Outcome; Patient Selection; Patients; Probability; Process; Prognostic Marker; Regulation; Regulatory T-Lymphocyte; Role; Solid Neoplasm; Staging; 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; new therapeutic target; novel strategies; outcome forecast; positional cloning; prevent; prognostic; public health relevance; response; trafficking; tumor; tumor growth; tumor progression; 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有关。实际上，与标准TNM UICC阶段相比，渗透程度是更好的预后预测指标。即使在全身存在大量肿瘤特异性效应细胞中，接受免疫疗法的肿瘤也经常避免破坏，因为免疫细胞没有到达肿瘤。但是，淋巴细胞浸润和预后之间关系的临床研究都没有解释免疫疗法的研究解释为什么有些患者的浸润程度很高，而另一些患者的浸润程度很低。淋巴细胞对浸润肿瘤的能力的预测对于评估癌症预后和选择可能对免疫疗法反应的患者的选择很重要。然而，尽管对淋巴细胞粘附在血管壁，尿和肿瘤的侵袭上的依次过程和分子有广泛的定义，但在个别患者中对此过程的预测是不可能的。我们已经确定了一种新的评估肿瘤浸润倾向的方法。我们表明，淋巴细胞浸润肿瘤的倾向是由宿主的基因组（患者）遗传控制的，因此可以通过分析任何正常组织的DNA而无需分析肿瘤组织来评估。该假设是基于意外发现，即在小鼠中，肿瘤浸润的存在和强度受到遗传控制。我们绘制了四个这样的遗传基因座，lynf1 -lynf4（lynf =淋巴细胞浸润）。这些基因座没有编码> 50个基因（粘附分子，趋化因子，基质金属蛋白酶等），这些基因以前已经推断为参与淋巴细胞运输和肿瘤浸润。因此，LYNF基因可能代表参与这些过程的新因素。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，并可能成为新的治疗靶标。这也将有助于避免肿瘤浸润低倾向的患者的免疫疗法，并导致其他疗法的个性化选择。为了研究这些基因的功能并鉴定它们的分子，我们将在短染色体片段（小于2-4 cm）中生成携带这些基因的先天线，以便可以在其他基因的干扰中分析它们的功能。我们将确定这些基因是否影响肿瘤的生长，确定某些淋巴细胞亚类选择性浸润，以及它们是在骨髓衍生的细胞中还是在肿瘤及其微环境中系统地进行。我们将至少鉴定一个lynf基因分子，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细胞，负责防御感染和癌症的淋巴细胞。但是，由于许多患者的未知原因，这些细胞在癌症组织内没有足够的数量，这可以增加侵袭和转移的可能性，缩短生存时间以及疫苗对癌症的有效性降低。我们发现在小鼠中是确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，以便能够将此发现应用于改善人类癌症的治疗。

项目成果

Genetic control of resistance to Trypanosoma brucei brucei infection in mice.

• DOI: 10.1371/journal.pntd.0001173
• 发表时间: 2011-06
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Síma M;Havelková H;Quan L;Svobodová M;Jarošíková T;Vojtíšková J;Stassen AP;Demant P;Lipoldová M
• 通讯作者: Lipoldová M