NK CELLS INDUCE DCI-MEDIATED ANTI-TUMOR IMMUNITY

Th 1和CTL驱动的细胞免疫被认为是对抗慢性炎症的最有效的防御。 细胞内感染和癌症。我们最近已经证明了一种新的Th 1和CTL促进机制的存在，基于适当激活的NK细胞诱导1型极化效应树突状细胞（DC 1 s）的能力。基于我们的初步观察，即人NK细胞可以增强DC的活化状态并诱导具有升高的IL-12产生能力的DC 1，我们打算检验NK细胞依赖的DC极化将支持针对肿瘤相关抗原的Th 1细胞和CTL的诱导的假设。此外，我们假设在体外由NK细胞及其可溶性产物诱导的DC 1在DC 1治疗的癌症患者中将作为肿瘤特异性应答的上级诱导剂。 I/II期临床试验。该项目将追求四个具体目标：具体目标1。确定能够诱导DC 1（DC 1 NK）的NK细胞的必要信号和特征; 具体目标2。表征NK诱导的DC 1 NK，并确定NK依赖性、DC 1 NK介导的免疫调节机制;具体目标3.证明在人体外模型中DC 1 NK是黑素瘤和结肠直肠癌特异性Th 1细胞和CTL的上级诱导剂（以控制通过IL-1b/TNF α/IL-6/PGE 2成熟的DC）;具体目的4.在I/II期临床试验（黑色素瘤和结直肠癌）中证明基于DC 1 NK的疫苗的可行性和免疫学有效性。

Th1- and CTL driven cellular immunity is thought to be the most effective defense against chronic intracellular infections and cancer. We have recently demonstrated the existence of a novel Th1- and CTL-promoting mechanism, based on the ability of the appropriately-activated NK cells to induce type-1 polarized effector dendritic cells (DC1s). Based on our PRELIMINARY OBSERVATIONS that human NK cells can enhance the activation state of DCs and induce DC1s with elevated IL-12-producing ability, we intend to test the hypothesis that NK cell-dependent DC polarization will support the induction of Th1 cells and CTLs against tumor-related antigens. Furthermore, we hypothesize that DC1 induced in vitro by NK cells and their soluble products will act as superior inducers of tumor-specific responses in DC1-treated cancer patients in phase I/II clinical trials. This project will pursue four Specific Aims: Specific Aim 1. Identify the requisite signals and characteristics of NK cells capable of inducing DC1 (DC1NK); Specific Aim 2. Characterize NK-induced DC1NK, and identify the mechanisms of NK-dependent, DC1NK-mediated immunoregulation; Specific Aim 3. Demonstrate that DC1NK are superior (to control DC matured by IL-lb/TNFa/IL-6/PGE2) inducers of melanoma- and colorectal cancer-specific Th1 cells and CTLs in human in vitro models; Specific Aim 4. Demonstrate the feasibility and immunologic efficacy of DC1NK-based vaccines in phase I/II clinical trials (melanoma and colorectal cancer).