Function of IRF8 in MDSC and T Cell Differentiation

 描述（由申请方提供）：癌细胞在免疫活性宿主中的持续存在部分是由于免疫应答的抑制，特别是细胞毒性T淋巴细胞（CTL）的抑制。这种抑制可能是由骨髓来源的抑制细胞或MDSC引起的。MDSC蓄积常见于人类癌症患者和荷瘤小鼠，特别是淋巴组织，包括脾、血液和骨髓。癌细胞可以使用失调的骨髓生成和由此产生的MDSC积累作为抑制CTL诱导的细胞毒性、逃避免疫监视和促进肿瘤生长的机制。CTL和MDSC之间的动态相互作用从而决定癌症是否会消退或进展。干扰素调节因子8（Interferon Regulatory Factor 8，IRF 8）是一种调节多种免疫细胞过程的关键转录因子，包括免疫细胞谱系，特别是骨髓细胞谱系分化。IRF 8缺失小鼠的一个关键表型是表型和功能上类似于肿瘤诱导的MDSC的MDSC的积累。此外，在生理条件下，IRF 8缺陷还损害CTL响应细胞因子信号传导的分化。因此，IRF 8是MDSC和CTL的关键调节因子。在我们的初步研究中，我们观察到尽管IRF 8缺失小鼠积累MDSC，但令人惊讶的是，仅在骨髓细胞中具有IRF 8缺陷的小鼠不存在显著的MDSC积累。相反，仅在T细胞中具有IRF 8缺陷的小鼠通过GM-CSF依赖性机制积累MDSC。基于我们的初步观察，我们假设IRF 8通过细胞外在机制控制骨髓生成，并通过细胞内在机制调节CTL分化，从而抑制MDSC抑制活性并促进抗肿瘤CTL免疫。为了检验我们的假设，我们将研究以下目的：1）确定IRF 8沉默是否通过MDSC积累促进肿瘤持续存在-包括同种异体移植物肿瘤生长;和2）测试IRF 8是否是体内抗原特异性CTL活化和分化的必要调节剂，如果是，这种调节是否发生在T细胞受体（TCR）依赖性机制中。该研究项目的成功完成有可能开发出一种基于IRF 8机制的治疗方法，以控制MDSC和CTL之间的相互作用，从而增强CTL在人类癌症免疫治疗中的抗癌免疫力。

 DESCRIPTION (provided by applicant): The persistence of cancer cells within an immune competent host occurs in part due to the suppression of the immune response, particularly of cytotoxic T lymphocytes (CTLs). This suppression may be caused by myeloid-derived suppressor cells, or MDSCs. MDSC accumulation is often seen in human cancer patients and tumor-bearing mice, particularly in lymphoid tissues including spleen, blood, and bone marrow. Cancer cells may use deregulated myelopoiesis and resultant MDSC accumulation as a mechanism of suppressing CTL-induced cytotoxicity, evading immune surveillance, and promoting tumor growth. The dynamic interactions between CTLs and MDSCs thereby determine whether cancer will regress or progress. Interferon Regulatory Factor 8 (IRF8) is a key transcription factor that regulates multiple immune cell processes, including immune cell lineage, particularly myeloid cell lineage differentiation. One key phenotype of IRF8 null mice is accumulation of MDSCs that phenotypically and functionally resemble tumor- induced MDSCs. In addition, IRF8 deficiency also impairs CTL differentiation in response to cytokine signaling under physiological conditions. IRF8 is thus a key regulator of both MDSCs and CTLs. In our preliminary studies, we observed that although IRF8 null mice accumulate MDSCs, surprisingly, mice with IRF8 deficiency only in myeloid cells do not present with significant MDSC accumulation. Instead, mice with IRF8 deficiency only in T cells accumulate MDSCs through a GM-CSF-dependent mechanism. Based on our preliminary observations, we hypothesize that IRF8 controls myelopoiesis through a cell-extrinsic mechanism and regulates CTL differentiation through a cell-intrinsic mechanism, thereby inhibiting MDSC suppressive activity and promoting anti-tumor CTL immunity. To test our hypothesis, we will investigate the following aims: 1) determine if IRF8 silencing promotes tumor persistence-including allograft tumor growth- through MDSC accumulation; and 2) test whether IRF8 is an essential regulator of antigen- specific CTL activation and differentiation in vivo, and if so, whether this regulation occurs in aT cell receptor (TCR) - dependent mechanism. Successful completion of this research project has the potential to develop an IRF8 mechanism-based therapy to control the interactions between MDSCs and CTLs, thereby strengthening CTL anti-cancer immunity in human cancer immunotherapy.