Tumor-Specific Chemokine Modulation in Colorectal Cancer Versus Melanoma

我们将测试这一假设，即DC和其他肿瘤相关细胞产生不同集合的 趋化因子(CK)和吸引功能不同的免疫细胞亚群在肿瘤中被确定- 具体方式由不同的炎症介质决定。此外，我们假设药理学上 通过对肿瘤CK环境的调节，可以选择性地促进疫苗接种的肿瘤进入。 诱导具有明确CK受体表达的1型效应T细胞(Jeff：Th1和CTL)，但不表达Tregs。 我们的目标是开发可靠的治疗方法，使用与肿瘤匹配的药物组合来 选择性地增强肿瘤病变内吸引Tef的CKs的产生，以促进 肿瘤免疫治疗的临床疗效。根据我们的初步数据，我们预计我们将能够 确定具有双选择性的组合处理：a)选择性地提高Jeff- 吸引CKs而不增强Treg吸引CKs；以及B)在肿瘤病变中优先有效，而是 而不是健康的组织。对比黑色素瘤和结直肠癌，肿瘤转移到相同的 器官(肝脏)，我们将确定肿瘤的组织类型与其位置的各自作用 植入测定局部CK的产生，将确定细胞和分子机制。 CK在健康组织、原发肿瘤和转移癌中的表达差异及其机制 这类组织对特定的CK调节剂的不同反应。 在特定的目标1中，我们将确定哪些肿瘤特异性炎症因子，选择性地与 黑色素瘤或结直肠癌，测定肿瘤相关细胞在体外产生的CK，并规定 功能不同的免疫细胞亚群的招募。我们将分析这些因素对 分离的DC和其他肿瘤相关细胞类型产生杰夫-吸引-而不是Treg- 吸引Cks，并优先吸引Te/f v.Treg细胞。在特定的AIM2内，我们将确定 结直肠癌、黑色素瘤和健康组织之间CK调节差异的机制，并将发展 纠正黑色素瘤和结直肠癌中Te/Fv-Treg之间平衡的方法 采用人体外肿瘤组织培养模型和小鼠体内原发和转移模型 肿瘤。在特定的目标3中，我们将进行临床前小鼠研究，以测试癌症的协同作用。 针对原发癌和转移癌的疫苗和趋化因子调节方案，随后是阶段 树突状细胞疫苗联合优先选择的肿瘤选择性CK-2治疗的临床试验 肝转移性结直肠癌和转移性黑色素瘤患者的调整方案。 相关性(请参阅说明)：

We will test the hypothesis that the ability of DCs and other tumor-associated cells to produce distinct sets of chemokines (CK)and to attract functionally different subsets of immune cells is determined in a tumor- specific manner by distinct inflammatory mediators. Furthermore, we hypothesize that pharmacological modulation of tumor CK environment can be used to selectively promote the tumor entry of the vaccination- induced type-1 effector T cells (Jeff: Th1 and CTL) with defined expression of CK receptors, but not Tregs. Our goal is to develop reliable treatments with tumor-matched combinations of pharmacologic agents to selectively enhance the production of the Teff-attracting CKs within tumor lesions, in order to promote the clinical efficacy of cancer immunotherapies. Based on our Preliminary data, we expect that we will be able to identify the combination treatments with double selectivity: A) selectively enhancing the production of Jeff- attracting CKs without enhancing Treg-attracting CKs; and B) preferentially effective in tumor lesions, rather than healthy tissues. Contrasting melanoma and colorectal cancer, the tumors metastasizing to the same organ (liver), we will determine the respective roles of the histological type of tumor versus the site of its implantation in determining local CK production, will identify the cellular and molecular mechanisms of different CK production between healthy tissues, primary and metastatic cancer, and the mechanisms of the differential responsiveness of such tissues to particular CK-modulating agents. Within Specific Aim 1, we will determine which tumor-specific inflammatory factors, selectively relevant to melanoma or to CRC,determine the CK production by tumor-associated cells in vitro and dictate the recruitment of functionally-different subsets of immune cells. We will analyze the impact of such factors on the ability of isolated DCs and other tumor-associated cell types to produce the Jeff-attracting- versus Treg- attracting CKs, and to preferentially attract Te/f v. Treg cells. Within Specific Aim2, we will determine the mechanisms of differences in CK regulation between CRC, melanoma, and healthy tissues, and will develop the methods to correct the balance between the Te/fv Treg-attracting CKs in melanoma and CRC tumors, using human ex vivo models of tumor explant cultures and mouse in vivo models of primary and metastatic tumors. Within Specific Aim 3, we will perform preclinical mouse studies testing the synergism of cancer vaccines and chemokine-regulatory regimens against primary and metastatic cancers, followed by phase clinical trials of selected therapies with DC-based vaccines combined with the prioritized tumor-selective CK- modulating regimens in patients with liver-metastatic CRC and patients with melanoma in transit. RELEVANCE (See instructions):