Modulation of tumor inflammatory factor for immune therapy

调节肿瘤炎症因子用于免疫治疗

• 批准号: 9754789
• 负责人: Shu-Hsia Chen
• 金额: $ 44.96万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 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/9754789
• 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; 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; Myeloid-derived suppressor cells; Neoplasm Metastasis; Neoplasm Transplantation; Phenotype; Play; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; T-Lymphocyte; TNF gene; Testing; Translating; Transmembrane Domain; Tumor Angiogenesis; Tumor Immunity; Tumor Tissue; Tumor-associated macrophages; angiogenesis; base; cancer immunotherapy; checkpoint therapy; chemokine; clinical translation; cytokine; hypoxia inducible factor 1; knock-down; macrophage; member; microbiome; monocyte; neoplastic cell; novel; novel therapeutics; pathogen; recruit; response; success; transcription factor; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

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。 肿瘤微环境与肿瘤发生。髓系抑制细胞与肿瘤相关 肿瘤微环境中的巨噬细胞()已被证明促进肿瘤进展和 转移。尽管T细胞检查点抑制疗法最初有望用于治疗癌症患者，但 TAMS和MDSCs建立的免疫抑制促肿瘤微环境仍然是主要的 取得完全成功的障碍。利用qPCR超阵列，我们鉴定了一种重要的肿瘤因子，CKLF样 Marvel跨膜结构域包含4(CMTM4)，是趋化素样因子超家族的成员， 它在人类和小鼠肿瘤细胞和组织中高度表达。初步研究表明，CMTM4 在肿瘤相关炎症的调节和抑制性的建立中起着重要作用 肿瘤微环境。CMTM4在肿瘤中的siRNA敲除(KD)导致肿瘤显著减少 多种肿瘤类型的生长和血管生成。髓系特异性CMTM4缺陷导致显著 在移植瘤模型中延缓肿瘤的发展。最有趣的是，来自CMTM4 KO的髓系细胞 小鼠倾向于M1经典的功能激活和成熟，这反过来在 炎性细胞因子和炎症相关转录因子(如IL-6、TNFα、IL-6)的调节 1beta、NFkappaB、HIF1pha、IRF5和IRF8)。我们假设CMTM4是控制 炎症信号，并随后通过募集和影响肿瘤微环境 MDSCs分化为“M2样”，交替激活的表型，促进血管生成和 免疫逃逸，从而促进肿瘤的进展。因此，CMTM4调节的调制 炎症反应可能会将免疫抑制的肿瘤微环境转变为免疫- 有利的一条。在这个提案中，我们将追求三个具体目标来验证我们的假设：1)CMTM4是关键 控制肿瘤炎症的驱动程序。2)通过CMTM4调节髓系细胞的功能。对中国传统文化的研究 CMTM4的细胞和分子作用机制对临床翻译至关重要。CMTM4 KD 能改变肿瘤微环境，增强抗肿瘤免疫，控制肿瘤细胞进展。 成功完成这些研究将使我们更好地理解我们在小鼠身上的发现 CMTM4可以翻译成人体研究。所获得的科学信息将对 靶向TAMS/MDSC逆转晚期恶性肿瘤相关的免疫抑制并促进 开发一种新的治疗模式来调节慢性炎症性疾病。