Modulation of tumor inflammatory factor for immune therapy

调节肿瘤炎症因子用于免疫治疗

基本信息

批准号：
9389597
负责人：
Shu-Hsia Chen
金额：
$ 46.16万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-22 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9389597
关键词：
Affect Antibodies Biological Process Blocking Antibodies Cancer Patient Cell Differentiation process Cell physiology Chronic Development Disease Exhibits Genes Human Immune Immune Evasion Immune checkpoint inhibitor Immunologic Factors Immunosuppression Immunosuppressive Agents Immunotherapy Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-6 Knockout Mice Malignant - descriptor Malignant Neoplasms Mediating Membrane Membrane Fluidity Membrane Microdomains Modality Modeling Molecular Mechanisms of Action Mus Myelogenous Myeloid Cells Neoplasm Metastasis Neoplasm Transplantation Phenotype Play Proteins Recruitment Activity Regulation Role Signal Pathway Signal Transduction Small Interfering RNA Suppressor-Effector T-Lymphocytes T-Lymphocyte TNF gene Testing Translating Transmembrane Domain Tumor Angiogenesis Tumor Immunity Tumor Tissue angiogenesis base cancer immunotherapy chemokine clinical translation cytokine hypoxia inducible factor 1 knock-down macrophage member microbiome monocyte neoplastic cell novel novel therapeutics pathogen response success transcription factor tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

The study of tumor-associated inflammatory factors is essential for determining the relationship between the tumor microenvironment and tumorigenesis. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAM) within the tumor microenvironment have been shown to promote tumor progression and metastasis. Despite the initial promise of T cell checkpoint inhibitor therapies in treating cancer patients, the immunosuppressive tumor-promoting microenvironment established by TAMs and MDSCs remains a major barrier to complete success. Using qPCR superarrays, we identified an important tumor factor, CKLF-like MARVEL transmembrane domain containing 4 (CMTM4), a member of the chemokine-like factor superfamily, which is highly expressed in human and mouse tumor cells and tissues. Preliminary studies showed that CMTM4 plays a significant role in the regulation of tumor-associated inflammation and establishment of a suppressive tumor microenvironment. siRNA knockdown (KD) of CMTM4 in tumor led to a significant reduction in tumor growth and angiogenesis in multiple tumor types. Myeloid specific CMTM4 deficiency results in significantly retarded tumor development in transplanted tumor models. Most interestingly, myeloid cells from CMTM4 KO mice skew toward M1 classical functional activation and maturation, which, in turn, plays an important role in the regulation of inflammatory cytokines and inflammation-related transcription factors (e.g. IL-6, TNFalpha, IL- 1beta, NFkappaB, HIF1alpha, IRF5, and IRF8). We hypothesize that CMTM4 is a key factor in controlling inflammatory signals and subsequently affects the tumor microenvironment through recruitment and differentiation of MDSCs toward an “M2-like”, alternatively activated, phenotype that promotes angiogenesis and immune evasion, thereby facilitating tumor progression. Therefore, modulation of CMTM4-regulated inflammatory responses may convert an immune-suppressive tumor microenvironment into an immune- conducive one. In this proposal, three specific aims will be pursued to test our hypothesis: 1) CMTM4 is the key driver that controls tumor inflammation. 2) Modulate the function of myeloid cells through CMTM4. Studies of the cellular and molecular mechanisms of action utilized by CMTM4 are critical for clinical translation. CMTM4 KD can alter the tumor microenvironment, enhance anti-tumor immunity, and control tumor cell progression. Successful completion of these studies will lead to a better understanding of how our findings with mouse CMTM4 can be translated to human studies. The scientific information gained will have a significant impact on targeting TAMs/MDSC to revert the immune suppression associated with advanced malignancies and facilitate development of a novel therapeutic modality for the regulation of chronic inflammatory diseases.

肿瘤相关炎症因子的研究对于确定肿瘤相关炎症因子之间的关系至关重要肿瘤微环境和肿瘤发生。骨髓源性抑制细胞（MDSC）和肿瘤相关。肿瘤微环境中的巨噬细胞（TAM）已被证明可以促进肿瘤进展和尽管 T 细胞检查点抑制剂疗法最初有望治疗癌症患者，但 TAM 和 MDSC 建立的免疫抑制促肿瘤微环境仍然是主要的使用 qPCR 超阵列，我们确定了一个重要的肿瘤因子，CKLF 样。 MARVEL 跨膜结构域包含 4 (CMTM4)，趋化因子样因子超家族的成员，初步研究表明，CMTM4在人和小鼠肿瘤细胞和组织中高表达。在调节肿瘤相关炎症和建立抑制性炎症反应中发挥重要作用肿瘤微环境中 CMTM4 的 siRNA 敲低（KD）导致肿瘤显着减少。多种肿瘤类型的生长和血管生成显着导致骨髓特异性 CMTM4 缺陷。最有趣的是，来自 CMTM4 KO 的骨髓细胞可延缓移植肿瘤模型中的肿瘤发育。小鼠倾向于 M1 经典功能激活和成熟，这反过来又在炎症细胞因子和炎症相关转录因子（例如 IL-6、TNFα、IL- 我们利用了 CMTM4 是控制的关键因素。炎症信号，随后通过募集和影响肿瘤微环境 MDSC 向“M2 样”、选择性激活、促进血管生成的表型分化免疫逃避，从而促进肿瘤进展，因此，调节 CMTM4 调节。炎症反应可能会将免疫抑制性肿瘤微环境转变为免疫抑制性肿瘤微环境。在本提案中，将追求三个具体目标来检验我们的假设：1）CMTM4 是关键。 2) 通过 CMTM4 调节骨髓细胞的功能。 CMTM4 利用的细胞和分子作用机制对于 CMTM4 KD 的临床转化至关重要。可以改变肿瘤微环境，增强抗肿瘤免疫，控制肿瘤细胞进展。成功完成这些研究将有助于更好地理解我们的小鼠研究结果 CMTM4可以转化为人类研究，所获得的科学信息将对人类研究产生重大影响。靶向 TAM/MDSC 以恢复与晚期恶性肿瘤相关的免疫抑制并促进开发一种调节慢性炎症疾病的新治疗方式。