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: 9891026
• 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/9891026
• 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.

项目概要 骨髓细胞，包括单核细胞和巨噬细胞，通常被激活以清除病原体并促进 免疫，但这些相同的细胞也可以在肿瘤微环境中重新编程，成为 肿瘤相关巨噬细胞（TAM），抑制抗肿瘤免疫并促进肿瘤生长 和转移。研究调查抗肿瘤“M1样”经典背后的生物学机制 成熟与促进肿瘤的“M2 样”替代激活相比具有显着的治疗潜力。 配对 Ig 样受体 B (PIR-B) 是一种主要在小鼠骨髓谱系上表达的受体，可抑制 免疫激活。白细胞免疫球蛋白样受体 B 亚家族 (LILRB) 代表人类 小鼠 PIR-B 的直系同源物。我们发现 PIR-B 维持肿瘤浸润典型的 M2 样表型 骨髓细胞。缺乏 PIR-B 的小鼠肿瘤负荷减少，并且浸润性 MDSC 谱图 类似于 M1 样经典激活表型。因此，调节骨髓细胞中的 LILRB 信号传导 可能提供控制肿瘤侵袭/进展的方法。我们的小组产生了一组抗体 针对 LILRB 家族成员并筛选它们在人类单核细胞来源的功能活性 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 抗体促进经典 M1 样激活。相应地，巨噬细胞下调 M2 相关的 lpha 同时抑制 IL-10 分泌，与 M1 经典一致 成熟。我们假设 LILRB 是一种重要的稳态调节因子，可抑制人类 单核细胞经典激活，从而在肿瘤进展和转移中发挥关键作用。三具体 追求的目标：1）通过PIRB/LILRB调节骨髓细胞的功能，促进抗肿瘤 回应。 2）LILRB控制肿瘤侵袭。 3) 通过培养M1来预防肿瘤侵袭/进展 巨噬细胞分化作为免疫检查点疗法。细胞和分子研究 LILRB 使用的作用机制对于临床转化至关重要。顺利完成这些 研究将有助于更好地理解我们对小鼠 PIRB 的研究结果如何转化为人类 LILRB。此外，LILRB阻断可以改变肿瘤微环境，增强抗肿瘤免疫力，并 控制肿瘤细胞的侵袭。这些发现可能会导致 TAM/MDSC 的新方法的发现 可以有针对性地对抗与晚期恶性肿瘤相关的免疫抑制。消融 免疫抑制和预防肿瘤侵袭应显着增强免疫疗法的疗效 用于治疗晚期转移性癌症的疗法。