Tumor cell antigen presentation to CD4 + T lymphocytes

肿瘤细胞抗原呈递给 CD4 T 淋巴细胞

基本信息

批准号：
6724891
负责人：
SUZANNE OSTRAND-ROSENBERG
金额：
$ 26.65万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE COUNTY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-07-01 至 2007-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6724891
关键词：
CD40 molecule MHC class II antigen antigen presentation breast neoplasms chemokine genetically modified animals helper T lymphocyte immunosuppression laboratory mouse metastasis neoplasm /cancer immunology neoplasm /cancer immunotherapy neoplasm /cancer surgery neoplasm /cancer vaccine nonhuman therapy evaluation transcription factor vaccine development

项目摘要

DESCRIPTION: (Adapted from applicant's abstract) Our long-term goal is to generate cell-based cancer vaccines for the treatment of established metastatic cancer, particularly metastatic breast cancer. Because CD4+ T lymphocytes are critical cells for optimal cell-mediated immunity, we have focused on making vaccines that activate tumor-specific CD4+ T cells. The vaccines are based on two hypotheses: 1) Tumor cells genetically modified to express syngeneic MHC class II, co-stimulatory, and T cell activation molecules directly present tumor-encoded antigens to CD4+ T cells; 2) Activation of tumor-specific CD4+ T cells facilitates activation of tumor-specific CD8+ T cells and results in potent anti-tumor immunity and long-term memory. Mechanistic and therapeutic studies support both hypotheses, and in a separate project we are translating this approach to the clinic. Although the vaccines have significant therapeutic efficacy against large burdens of widely disseminated, spontaneous metastatic cancer, some mice are non-responders and although survival time for others is significantly extended, most mice still die. As we adapt the vaccines to the clinic, it is highly desirable to continue developing new approaches in innovative animal models, so that we can constantly input improved strategies to the translational studies. Further development is dependent on understanding the underlying mechanisms by which the vaccines stimulate immunity. Studies, therefore, have also focused on examining basic aspects of antigen presentation by the vaccines. To further improve and test the vaccines in mice, the following therapeutic and mechanistic questions will be addressed: 1) Do the MHC class Il-based vaccines protect very high risk mice from developing mammary cancer? 2) Can expression of transcriptional regulatory elements down-regulate Invariant chain and convert MHC class II+Ii+DM+ tumor cells to vaccines? 3) How do the cell-based vaccines present MHC class 11-restricted, endogenously synthesized tumor antigens? 4) What is the role of the vaccine cells in induction of anti-tumor immunity? Which effector cells, cytokines, and chemokines are induced during therapy? 5) Does tumor burden correlate with tumor-induced immuno-suppression? Does surgical removal of primary tumor reverse mmuno-suppression?

描述：（改编自申请人的摘要）我们的长期目标是产生基于细胞的癌症疫苗，用于治疗已确定的转移性癌症癌症，特别是转移性乳腺癌。因为 CD4+ T 淋巴细胞最佳细胞介导免疫的关键细胞，我们专注于制造激活肿瘤特异性 CD4+ T 细胞的疫苗。疫苗是基于两个假设：1) 肿瘤细胞经过基因修饰以表达同基因 MHC II类、共刺激和T细胞激活分子直接存在 CD4+ T 细胞的肿瘤编码抗原； 2) 肿瘤特异性CD4+ T的激活细胞促进肿瘤特异性 CD8+ T 细胞的激活，并导致有效的抗肿瘤免疫力和长期记忆。机制和治疗研究支持这两种假设，并且在一个单独的项目中我们正在翻译这种方法走向临床。尽管疫苗具有显着的治疗作用对广泛播散、自发转移的巨大负担的功效对于癌症，一些小鼠没有反应，尽管其他小鼠的生存时间很长显着延长，大多数小鼠仍然死亡。当我们调整疫苗以适应临床上，非常需要继续开发新的方法创新的动物模型，让我们不断输入改进的策略到转化研究。进一步的发展取决于理解疫苗刺激免疫力的基本机制。研究，因此，还重点研究了抗原呈递的基本方面通过疫苗。为了进一步改进和测试小鼠疫苗，将解决以下治疗和机制问题：1）基于 MHC II 类的疫苗可保护高风险小鼠免于乳腺发育癌症？ 2）转录调控元件的表达是否会下调不变链并将MHC II类+Ii+DM+肿瘤细胞转化为疫苗？ 3）如何基于细胞的疫苗是否存在 MHC 11 类限制性内源性合成肿瘤抗原？ 4）疫苗细胞的作用是什么？诱导抗肿瘤免疫？哪些效应细胞、细胞因子和治疗过程中会诱导趋化因子吗？ 5) 肿瘤负荷与以下因素相关吗肿瘤引起的免疫抑制？是否需要手术切除原发肿瘤逆转免疫抑制？

项目成果

期刊论文数量（39）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Beta 2M-/- knockout mice contain low levels of CD8+ cytotoxic T lymphocyte that mediate specific tumor rejection.

Beta 2M-/- 基因敲除小鼠含有低水平的 CD8 细胞毒性 T 淋巴细胞，可介导特异性肿瘤排斥。

DOI：
发表时间：
1993
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Lamousé-Smith,E;Clements,VK;Ostrand-Rosenberg,S
通讯作者：
Ostrand-Rosenberg,S

Rejection of allogeneic tumor is not determined by host responses to MHC class I molecules and is mediated by CD4-CD8+ T lymphocytes that are not lytic for the tumor.

同种异体肿瘤的排斥不是由宿主对 MHC I 类分子的反应决定的，而是由不溶解肿瘤的 CD4-CD8 T 淋巴细胞介导的。

DOI：
10.1016/0008-8749(91)90319-7
发表时间：
1991
期刊：
Cellular immunology
影响因子：
4.3
作者：
Cole,GA;Ostrand-Rosenberg,S
通讯作者：
Ostrand-Rosenberg,S

MHC class II-transfected tumor cells directly present antigen to tumor-specific CD4+ T lymphocytes.

DOI：
发表时间：
1998-01
期刊：
Journal of immunology
影响因子：
4.4
作者：
Todd D. Armstrong;V. Clements;S. Ostrand-Rosenberg
通讯作者：
Todd D. Armstrong;V. Clements;S. Ostrand-Rosenberg

Tumor-specific immunity can be enhanced by transfection of tumor cells with syngeneic MHC-class-II genes or allogeneic MHC-class-I genes.

通过用同源MHC-II类基因或同种异体MHC-I类基因转染肿瘤细胞可以增强肿瘤特异性免疫。

DOI：
10.1002/ijc.2910470714
发表时间：
1991
期刊：
International journal of cancer. Supplement = Journal international du cancer. Supplement
影响因子：
0
作者：
Ostrand-Rosenberg,S;Roby,C;Clements,VK;Cole,GA
通讯作者：
Cole,GA

Gene-modified tumor cells as cellular vaccine.

基因修饰的肿瘤细胞作为细胞疫苗。