LILRB modulates tumor microenvironment and promotes tumor progression

LILRB调节肿瘤微环境并促进肿瘤进展

基本信息

  • 批准号:
    10053709
  • 负责人:
  • 金额:
    $ 43.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 髓系细胞,包括单核细胞和巨噬细胞,通常被激活以清除病原体和促进 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),它们抑制抗肿瘤免疫并促进肿瘤生长 和转移。研究抗肿瘤“类M1”经典药物的生物学机制 成熟与促进肿瘤的“M2样”交替激活具有显著的治疗潜力。 配对Ig样受体B(PIR-B)是一种主要表达在小鼠髓系上的受体,它抑制 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的直系同源基因。我们发现PIR-B保持了肿瘤浸润性的典型的M2样表型 髓系细胞。PIR-B基因缺陷的小鼠肿瘤负担减轻,MDSC图谱呈浸润性 类似于M1类经典激活表型。因此,LILRB信号在髓系细胞中的调节 可能为控制肿瘤的侵袭/进展提供一种手段。我们的团队产生了一组抗体 抗LILRB家族成员,并筛选他们在人单核细胞来源的功能活性 巨噬细胞为基础的检测。与我们在小鼠身上的发现一致,我们观察到LILRB具有拮抗作用 抗体促进经典的类M1激活。一致地,巨噬细胞下调与M2相关的 同时抑制IL-10的分泌,这一特征与M1经典的一致 成熟。我们假设LILRB是一种重要的动态平衡调节剂,它抑制人类 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。三个具体的 目的:1)通过PirB/LILRB调节髓系细胞的功能,促进抗肿瘤 回应。2)LILRB抑制肿瘤侵袭。3)通过培养M1防止肿瘤侵袭/进展 巨噬细胞分化作为一种免疫检查点疗法。细胞和分子的研究 LILRB使用的作用机制对临床翻译至关重要。成功完成这些任务 研究将使我们更好地理解我们在小鼠PirB上的发现如何转化为人类 LILRB。此外,阻断LILRB还可以改变肿瘤微环境,增强抗肿瘤免疫,并 控制肿瘤细胞侵袭。这些发现可能导致发现TAMS/MDSC的新方法 可以靶向对抗与晚期恶性肿瘤相关的免疫抑制。烧蚀 免疫抑制和预防肿瘤侵袭应显著增强免疫基础的疗效 晚期转移性癌症的治疗方法。

项目成果

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Shu-Hsia Chen其他文献

Shu-Hsia Chen的其他文献

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{{ truncateString('Shu-Hsia Chen', 18)}}的其他基金

Development of Therapeutic Cancer Vaccine
治疗性癌症疫苗的开发
  • 批准号:
    10324856
  • 财政年份:
    2022
  • 资助金额:
    $ 43.6万
  • 项目类别:
Mechanism of Intratumoral Transport of Particulate Drugs
颗粒药物的瘤内转运机制
  • 批准号:
    10531257
  • 财政年份:
    2018
  • 资助金额:
    $ 43.6万
  • 项目类别:
Mechanism of Intratumoral Transport of Particulate Drugs
颗粒药物的瘤内转运机制
  • 批准号:
    10310460
  • 财政年份:
    2018
  • 资助金额:
    $ 43.6万
  • 项目类别:
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
  • 财政年份:
    2017
  • 资助金额:
    $ 43.6万
  • 项目类别:
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:
    9389597
  • 财政年份:
    2017
  • 资助金额:
    $ 43.6万
  • 项目类别:
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
  • 财政年份:
    2016
  • 资助金额:
    $ 43.6万
  • 项目类别:
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:
    9599920
  • 财政年份:
    2016
  • 资助金额:
    $ 43.6万
  • 项目类别:
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:
    10310494
  • 财政年份:
    2016
  • 资助金额:
    $ 43.6万
  • 项目类别:
Intervention of Immune Tolerance by Small Molecules
小分子干预免疫耐受
  • 批准号:
    8704475
  • 财政年份:
    2008
  • 资助金额:
    $ 43.6万
  • 项目类别:
Intervention of Immune Tolerance by Small Molecules
小分子干预免疫耐受
  • 批准号:
    9068841
  • 财政年份:
    2008
  • 资助金额:
    $ 43.6万
  • 项目类别:

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