Inactivation of Cytotoxic Effectors in Oral Carcinomas

口腔癌中细胞毒性效应器的失活

• 批准号: 6765759
• 负责人: ANAHID JEWETT
• 金额: $ 3.98万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6765759
• 关键词: DNA binding protein; JUN kinase; apoptosis; biological signal transduction; carcinoma; cell cell interaction; cytokine receptors; cytotoxic T lymphocyte; cytotoxicity; human tissue; immunosuppression; interferon gamma; natural killer cells; neoplasm /cancer immunology; neoplastic cell; neoplastic process; nuclear factor kappa beta; oral pharyngeal neoplasm; protein tyrosine kinase; receptor expression; transforming growth factors; tumor necrosis factor alpha

DESCRIPTION: The long-term objective of this application is to determine whether the initiation and progression of oral carcinomas in vivo is due to the induction of functional inactivation and cell death of Natural Killer cells. Human carcinomas of the head and neck and the oral cavity induce the least detectable cell-mediated anti-tumor immune responses, and decreased frequencies of proliferating lymphocytes have been observed in the peripheral blood and tumor tissue of oral cancer patients. More importantly, regressing oral tumors contain significantly larger numbers of functional NK cells when compared to those associated with primary tumors. Thus, the central hypothesis is that the initiation of NK cell apoptotic signaling by factors secreted from the NK cells or elaborated by oral cancer cells during their interaction will result in the inactivation of NK cell cytotoxic function, thereby enhancing the survival of oral carcinoma cells. To delineate the mechanisms by which Natural Killer cells lose their cytotoxic function and undergo apoptotic cell death in the presence of oral cancer cells, the following will be examined: 1. The role of oral tumor cell induced TNF-alpha release from NK cells in the absence of IFN-gamma secretion in inactivation and cell death of NK cells. There are also plans to study the effect of oral tumor cells on inhibition of TNF receptor associated protein (TRAFs) and NFkappaB functions in NK cells. 2. The effect of oral tumor cell elaborated TGF-beta on the inhibition of NFkappaB activity in NK cells, and subsequent induction of NK cell inactivation and cell death. 3. The roles of oral tumor cell induced stress related c-jun N-terminal kinase (JNK) and protein tyrosine phosphatase 1C (PTP1C) signaling in NK cells and in the regulation of TNF-alpha and NFkappaB and induction of NK cell inactivation and cell death by oral carcinoma cells. 4. The differential effects of sensitive and resistant oral carcinoma cells on NK cell inactivation and cell death. 5. The effect of patient derived oral tumor cells in NK cell inactivation and cell death. Using both in vitro established oral tumor lines and in vivo studies utilizing tumor tissues and immune cells from individuals with cancer of the oral cavity, the exact mechanisms by which oral carcinoma cells exert an immunosuppressive effect on NK cells will be examined. Understanding the mechanisms by which NK cells become functionally inactivated and undergo cell death will enable design strategies to reverse such inactivation and ensure effective immunity against oral tumor cells.

描述：本申请的长期目标是确定 口腔癌在体内的发生和发展是否是由于 诱导自然杀伤细胞的功能失活和细胞死亡。 头颈部和口腔的人类癌诱导最少的 可检测的细胞介导的抗肿瘤免疫应答， 在外周血中观察到淋巴细胞增殖， 口腔癌患者的肿瘤组织。更重要的是， 含有显著更多数量的功能性NK细胞， 与原发性肿瘤相关的。因此，中心假设是， 由NK细胞分泌的因子引发NK细胞凋亡信号传导 或在它们相互作用过程中被口腔癌细胞加工， NK细胞的细胞毒性功能失活，从而增强 口腔癌细胞为了描述自然杀伤细胞 失去其细胞毒性功能，并在存在下经历凋亡性细胞死亡 口腔癌细胞，将检查以下内容：1.口腔肿瘤的作用 在IFN-γ不存在的情况下，细胞诱导的TNF-α从NK细胞释放 NK细胞的失活和细胞死亡中的分泌。还计划 口腔肿瘤细胞对肿瘤坏死因子受体相关抑制作用的研究 蛋白（TRAF）和NF κ B在NK细胞中的功能。2.口腔肿瘤的影响 细胞阐述了TGF-β对NK细胞中NF κ B活性的抑制， 以及随后诱导NK细胞失活和细胞死亡。3.的角色 口腔癌细胞诱导的应激相关c-jun N-末端激酶（JNK）和 蛋白酪氨酸磷酸酶1C（PTP 1C）信号在NK细胞和 调节TNF-α和NF κ B，诱导NK细胞失活， 口腔癌细胞死亡。4.敏感性的差异效应 和耐药口腔癌细胞对NK细胞失活和细胞死亡的影响。5. 口腔癌患者源性肿瘤细胞对NK细胞失活及细胞增殖的影响 死亡使用体外建立的口腔肿瘤细胞系和体内研究 利用来自患有癌症的个体的肿瘤组织和免疫细胞， 口腔，口腔癌细胞发挥作用的确切机制， 将检查对NK细胞的免疫抑制作用。了解 NK细胞在功能上失活并经历细胞凋亡的机制 死亡将使设计策略能够逆转这种失活， 对口腔肿瘤细胞有效免疫。

项目成果

Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice.

• DOI: 10.1007/s00262-016-1822-9
• 发表时间: 2016-07
• 期刊: Cancer immunology, immunotherapy : CII
• 作者: Kozlowska AK;Kaur K;Topchyan P;Jewett A
• 通讯作者: Jewett A

Tumor-infiltrating immune cells: triggers for tumor capsule disruption and tumor progression?

• DOI: 10.7150/ijms.5798
• 发表时间: 2013
• 期刊: International journal of medical sciences
• 影响因子: 3.6
• 作者: Jiang B;Mason J;Jewett A;Liu ML;Chen W;Qian J;Ding Y;Ding S;Ni M;Zhang X;Man YG
• 通讯作者: Man YG

Defective Patient NK Function Is Reversed by AJ2 Probiotic Bacteria or Addition of Allogeneic Healthy Monocytes.

患者NK功能有缺陷会被AJ2益生菌细菌或同种异体健康的单核细胞逆转。

• DOI: 10.3390/cells11040697
• 发表时间: 2022-02-16
• 期刊: Cells
• 影响因子: 6
• 作者: Ko MW;Kaur K;Safaei T;Chen W;Sutanto C;Wong P;Jewett A
• 通讯作者: Jewett A

Resistance to cytotoxicity and sustained release of interleukin-6 and interleukin-8 in the presence of decreased interferon-γ after differentiation of glioblastoma by human natural killer cells.

• DOI: 10.1007/s00262-016-1866-x
• 发表时间: 2016-09
• 期刊: Cancer immunology, immunotherapy : CII
• 作者: Kozlowska AK;Tseng HC;Kaur K;Topchyan P;Inagaki A;Bui VT;Kasahara N;Cacalano N;Jewett A
• 通讯作者: Jewett A

Tumor induced inactivation of natural killer cell cytotoxic function; implication in growth, expansion and differentiation of cancer stem cells.

• DOI: 10.7150/jca.2.443
• 发表时间: 2011
• 期刊: Journal of Cancer
• 影响因子: 3.9
• 作者: Jewett A;Tseng HC
• 通讯作者: Tseng HC