LILRB modulates tumor microenvironment and promotes tumor progression

LILRB调节肿瘤微环境并促进肿瘤进展

• 批准号: 10053709
• 负责人: Shu-Hsia Chen
• 金额: $ 43.6万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053709
• 关键词: ANGPTL2 gene; Ablation; Affinity; Antibodies; Antitumor Response; Binding; Biological; Biological Assay; Biophysics; Breast Cancer Cell; Breast Cancer Model; Cancer Patient; Cell Differentiation process; Cells; Cellular Assay; Disseminated Malignant Neoplasm; Environment; Family member; Fostering; Foundations; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Immune checkpoint inhibitor; Immunity; Immunoglobulins; Immunosuppression; Immunotherapy; Interleukin-10; Interleukin-4; Laboratories; Lead; Leukocytes; Ligands; Macrophage Colony-Stimulating Factor; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Modeling; Molecular Mechanisms of Action; Mouse Mammary Tumor Virus; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Orthologous Gene; PTPN6 gene; Phenotype; Phosphoric Monoester Hydrolases; Play; Population; Regulation; Role; Signal Pathway; Signal Transduction; Structure; T-Lymphocyte; Therapeutic; Translating; Tumor Burden; Tumor Cell Invasion; Tumor Immunity; Tumor-associated macrophages; Tumorigenicity; base; cancer immunotherapy; cancer invasiveness; checkpoint therapy; clinical translation; combat; cytokine; design; immune activation; in vivo; macrophage; malignant breast neoplasm; monocyte; novel; pathogen; prevent; receptor; response; scavenger receptor; success; tumor; tumor growth; tumor microenvironment; tumor progression

Project Summary Myeloid cells, including monocytes and macrophages, are classically activated to clear pathogens and promote immunity, but these same cells can also be reprogrammed within the tumor microenvironment to become tumor-associated macrophages (TAMs), where they suppress anti-tumor immunity and promote tumor growth and metastasis. Studies investigating the biological mechanisms behind anti-tumor “M1-like” classical maturation versus tumor-promoting “M2-like” alternative activation possess significant therapeutic potential. Paired Ig-like receptor B (PIR-B), a receptor mainly expressed on myeloid lineages in mice, suppresses immune activation. The leukocyte immunoglobulin-like receptor subfamily B (LILRB) represents the human ortholog of mouse PIR-B. We found that PIR-B maintains the M2-like phenotype typical of tumor infiltrating myeloid cells. Mice deficient in PIR-B have reduced tumor burdens and an infiltrating MDSC profile that resembles the M1-like classical activation phenotype. Therefore, modulation of LILRB signaling in myeloid cells may provide a means for controlling tumor invasion/progression. Our group generated a panel of antibodies against LILRB family members and screened them for functional activity in human monocyte-derived macrophage cell-based assays. Consistent with our findings in mice, we observed that LILRB antagonistic antibodies promote classical M1-like activation. Concordantly, macrophages down-regulate M2-associated lpha while suppressing IL-10 secretion, a profile consistent with M1 classical maturation. We hypothesize that LILRB is an important homeostatic regulator that suppresses human monocyte classical activation, thereby playing a key role in tumor progression and metastases. Three specific aims will be pursued: 1) Modulate the function of myeloid cells through PIRB/LILRB to promote anti-tumor responses. 2) LILRB controls tumor invasion. 3) Prevent tumor invasion/progression by fostering M1 macrophage differentiation as an immune checkpoint therapy. Studies of the cellular and molecular mechanisms of action utilized by LILRB are critical for clinical translation. Successful completion of these studies will lead to a better understanding of how our findings with mouse PIRB can be translated to human LILRB. Furthermore, LILRB blockade can alter the tumor microenvironment, enhance anti-tumor immunity, and control tumor cell invasion. These findings may lead to the discovery of novel means by which TAMs/MDSC can be targeted to combat the immune suppression associated with advanced malignancies. Ablation of immune suppression and preventing tumor invasion should significantly augment the efficacy of immune-based therapies for the treatment of advanced metastatic cancer.

项目摘要 髓样细胞，包括单核细胞和巨噬细胞，经典地激活以清除病原体并促进 免疫力，但是这些相同的细胞也可以在肿瘤微环境中重新编程 肿瘤相关巨噬细胞（TAM），它们抑制抗肿瘤免疫学并促进肿瘤生长 和转移。研究研究了抗肿瘤“ M1样”经典的生物学机制 成熟与促进肿瘤的“ M2样”替代激活潜在的重要治疗潜力。 成对的Ig样受体B（PIR-B），一种主要在小鼠中髓样谱系上表达的受体，抑制 免疫激活。白细胞免疫球蛋白样受体亚家族B（lilrb）代表人类 小鼠PIR-B的直系同源物。我们发现PIR-B保持了典型的肿瘤浸润的M2样表型 髓样细胞。缺乏PIR-B的小鼠减少了肿瘤伯良和浸润的MDSC概况 类似于M1样的经典激活表型。因此，髓样细胞中LILRB信号的调节 可以提供控制肿瘤侵袭/进展的手段。我们的小组生成了一组抗体 反对LILRB家族成员，并筛选他们在人单核细胞中的功能活动 基于巨噬细胞的测定。与我们在小鼠中的发现一致，我们观察到LILRB拮抗作用 抗体促进经典M1样激活。一致，巨噬细胞下调M2相关 lpha抑制IL-10分泌时，与M1经典一致的配置文件 成熟。我们假设LILRB是抑制人类的重要稳态调节器 单核细胞经典激活，从而在肿瘤进展和转移酶中起关键作用。三个具体 将追求目标：1）通过PIRB/LILRB调节髓样细胞的功能以促进抗肿瘤 回答。 2）LILRB控制肿瘤侵袭。 3）通过培养M1来预防肿瘤侵袭/进展 巨噬细胞分化为免疫切除点疗法。细胞和分子的研究 LILRB使用的作用机制对于临床翻译至关重要。这些成功完成 研究将使人们更好地了解我们对小鼠PIRB的发现如何转化为人类 Lilrb。此外，LILRB封锁可以改变肿瘤微环境，增强抗肿瘤免疫组织化学，并 控制肿瘤细胞侵袭。这些发现可能导致发现TAMS/MDSC的新颖手段 可以针对与晚期恶性肿瘤有关的免疫抑制。消融 免疫抑制和预防肿瘤侵袭应显着提高免疫基的效率 治疗晚期转移性癌症的疗法。