Tumor cell antigen presentation to CD4 + T lymphocytes

描述：（摘自申请人摘要）我们的长期目标是 产生基于细胞的癌症疫苗，用于治疗已建立的转移性 癌症，特别是转移性乳腺癌。因为CD4+ T淋巴细胞是 关键细胞的最佳细胞介导的免疫力，我们一直专注于使 激活肿瘤特异性CD4+ T细胞的疫苗。疫苗是基于 两种假设：1）经遗传修饰以表达同源MHC的肿瘤细胞 II类共刺激分子和T细胞活化分子直接呈递 2）肿瘤特异性CD4+ T细胞的活化 细胞促进肿瘤特异性CD8+ T细胞的活化， 强大的抗肿瘤免疫力和长期记忆力。机制和治疗 研究支持这两种假设，在一个单独的项目中，我们正在翻译 这种方法在诊所。虽然疫苗具有显著的治疗效果， 对广泛传播、自发转移性 癌症，一些小鼠是无反应者，尽管其他小鼠的生存时间是 即使时间延长，大多数小鼠仍然死亡。当我们使疫苗适应 在临床上，非常希望继续开发新的方法， 创新的动物模型，这样我们就可以不断地输入改进的策略， 到翻译研究。进一步的发展取决于理解 疫苗刺激免疫力的潜在机制。研究， 因此，也集中于研究抗原呈递的基本方面， 被疫苗。为了进一步改进和在小鼠中测试疫苗， 以下治疗和机制问题将得到解决：1）做 基于MHC II类的疫苗保护极高风险小鼠免受乳腺发育 癌症吗2)转录调控元件的表达能下调 不变链和转化MHC II类+Ii+DM+肿瘤细胞的疫苗？3)如何 基于细胞的疫苗是否内源性地呈递MHC 11类限制性抗原 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， 趋化因子在治疗过程中会被诱导吗5)肿瘤负荷是否与 肿瘤引起的免疫抑制手术切除原发肿瘤 反向免疫抑制

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?