Host's Genes that Control Lymphocyte Infiltration of Tumors

描述（由申请方提供）：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，高度的肿瘤浸润与较好的预后相关。事实上，浸润程度是比标准TNM UICC分期更好的预后预测指标。即使在大量肿瘤特异性效应细胞的全身存在下，接受免疫治疗的肿瘤通常也会逃脱破坏，因为免疫细胞不会到达肿瘤。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，都不能解释为什么有些患者浸润程度高，而另一些患者浸润程度低。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是重要的。然而，尽管对淋巴细胞粘附于血管壁、渗出和肿瘤侵袭的顺序过程和分子有广泛的定义，但对个体患者中该过程的结果的预测尚不可能。我们已经确定了一种新的方法来评估个体的肿瘤浸润倾向。我们表明，淋巴细胞的肿瘤浸润倾向是由宿主（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进行评估，而无需分析肿瘤组织。这一假设是基于一个意想不到的发现，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位点，Lynf 1-Lynf 4（Lynf =淋巴细胞浸润）。这些基因座不编码> 50种基因中的任何一种（粘附分子、趋化因子、基质金属蛋白酶等）先前推断其参与淋巴细胞运输和肿瘤浸润。因此，Lynf基因可能代表了一组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点。这也将有助于避免对肿瘤浸润倾向低的患者进行免疫治疗，并导致对其他治疗方法的个性化选择。为了研究这些基因的功能并从分子水平上鉴定它们，我们将产生在短染色体片段（小于2- 4cM）中携带这些基因的同源系，以便可以在几乎不受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源性细胞中系统性地或局部地在肿瘤及其微环境中起作用。我们将在分子水平上识别出至少一个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细胞，淋巴细胞负责防御感染和癌症。然而，由于未知的原因，在许多患者中，这些细胞在癌组织中的数量不足，这会增加侵袭和转移的可能性，缩短生存时间，降低癌症疫苗的有效性。我们发现，在小鼠中有基因决定淋巴细胞是否会侵入癌症，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善人类癌症的治疗。

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.