Effect of tumor cell glutamine metabolism on anti-tumor immunity in TNBC

TNBC肿瘤细胞谷氨酰胺代谢对抗肿瘤免疫的影响

基本信息

  • 批准号:
    10219207
  • 负责人:
  • 金额:
    $ 49.32万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-17 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ ABSTRACT Breast cancer is the most common malignancy among western women. Although adjuvant and molecularly targeted therapies significantly improve patient survival in some molecular subtypes of breast cancer, the prognosis of triple-negative/basal-like breast cancer (TNBC) remains grim, due to lack of identification of oncogenic drivers. In searching of cancer vulnerability, it was discovered that TNBC is especially dependent on glutamine metabolism, likely due to up- regulation of the glutamine transporter, ASCT2/SLC1A5, and glutaminase, GLS, representing the rate-limiting steps in glutamine consumption. Despite the interest in targeting glutaminolysis in TNBC, it is unclear how global inhibition of glutamine metabolism will affect immune cells in the tumor microenvironment, particularly given that rapidly proliferating tumor infiltrating lymphocytes (TILs) require glutaminolysis to supply macromolecules for cell growth. Specifically, the competition between tumor cells and TILs for glutamine has not been investigated thus far, but is likely to be important for anti-tumor immunity. We have generated preliminary data providing evidence that knockout of GLS specifically in tumor cells increases glutamine concentration in the tumor interstitial fluid and enhances cytotoxic CD8 T lymphocyte activities. The above effects are abrogated in immune-deficient mice, suggesting that adaptive immunity plays a critical role. In addition, pharmacologic inhibition of the glutamine transporter, ASCT2, selectively targeting tumor cells while enhancing TIL function. Based on these findings, we hypothesize that (1) tumor cells outcompete TILs for glutamine to sustain their proliferative programs while simultaneously suppressing antitumor immune response, and (2) selectively targeting glutamine metabolism in tumor cells enhances antitumor immunity. To test these hypotheses, we will first test glutamine competition between tumor cells and TILs and how this competition affects tumor growth, metastasis, and anti-tumor immune responses (Aim 1). We will also define how metabolic changes in GLS loss specifically in tumor cells impact T cell recruitment and activation in situ by MALDI-imaging mass spectrometry (Aim 2). Finally, we will evaluate in vivo pharmacological targeting of glutamine transporter and glutaminase for treating TNBC (Aim 3). The success of the project will elucidate a long-standing issue whether there is a metabolic competition for glutamine between tumor cells and infiltrating lymphocytes, and leverage the knowledge for developing new therapeutic strategies for treatment of glutamine-addicted cancer.
项目摘要/摘要

项目成果

期刊论文数量(0)
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Mark R Boothby其他文献

Mark R Boothby的其他文献

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{{ truncateString('Mark R Boothby', 18)}}的其他基金

Antibody quality and germinal center requirements for peroxisomal function in lymphocytes
淋巴细胞过氧化物酶体功能的抗体质量和生发中心要求
  • 批准号:
    10469589
  • 财政年份:
    2021
  • 资助金额:
    $ 49.32万
  • 项目类别:
Antibody quality and germinal center requirements for peroxisomal function in lymphocytes
淋巴细胞过氧化物酶体功能的抗体质量和生发中心要求
  • 批准号:
    10318012
  • 财政年份:
    2021
  • 资助金额:
    $ 49.32万
  • 项目类别:
Effect of tumor cell glutamine metabolism on anti-tumor immunity in TNBC
TNBC肿瘤细胞谷氨酰胺代谢对抗肿瘤免疫的影响
  • 批准号:
    10430078
  • 财政年份:
    2020
  • 资助金额:
    $ 49.32万
  • 项目类别:
Effect of tumor cell glutamine metabolism on anti-tumor immunity in TNBC
TNBC肿瘤细胞谷氨酰胺代谢对抗肿瘤免疫的影响
  • 批准号:
    10656440
  • 财政年份:
    2020
  • 资助金额:
    $ 49.32万
  • 项目类别:
Manipulating & imaging nutrient micro-milieux as B cells effect humoral immunity
操纵
  • 批准号:
    10529278
  • 财政年份:
    2019
  • 资助金额:
    $ 49.32万
  • 项目类别:
Manipulating & imaging nutrient micro-milieux as B cells effect humoral immunity
操纵
  • 批准号:
    10062829
  • 财政年份:
    2019
  • 资助金额:
    $ 49.32万
  • 项目类别:
Manipulating & imaging nutrient micro-milieux as B cells effect humoral immunity
操纵
  • 批准号:
    9889587
  • 财政年份:
    2019
  • 资助金额:
    $ 49.32万
  • 项目类别:
Manipulating & imaging nutrient micro-milieux as B cells effect humoral immunity
操纵
  • 批准号:
    10306395
  • 财政年份:
    2019
  • 资助金额:
    $ 49.32万
  • 项目类别:
Fit to remember? B cell metabolic 'fitness', AMPK & recall antibody responses
适合记住吗?
  • 批准号:
    9204785
  • 财政年份:
    2015
  • 资助金额:
    $ 49.32万
  • 项目类别:
Fit to remember? B cell metabolic 'fitness', AMPK & recall antibody responses
适合记住吗?
  • 批准号:
    8888712
  • 财政年份:
    2015
  • 资助金额:
    $ 49.32万
  • 项目类别:

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