Tumor cell antigen presentation to CD4 + T lymphocytes

描述：(改编自申请者摘要)我们的长期目标是 生产细胞为基础的癌症疫苗用于治疗已确定的转移 癌症，尤其是转移性乳腺癌。因为CD4+T淋巴细胞是 对于最佳细胞免疫的关键细胞，我们一直专注于使 激活肿瘤特异性CD4+T细胞的疫苗。这些疫苗是基于 两个假设：1)转基因的肿瘤细胞表达同基因的MHC II类、共刺激分子和T细胞激活分子直接存在 肿瘤编码的CD4+T细胞抗原；2)肿瘤特异性CD4+T细胞的活化 细胞促进肿瘤特异性CD8+T细胞的激活并导致 强大的抗肿瘤免疫力和长期记忆力。机械性和治疗性 研究支持这两个假设，在另一个单独的项目中，我们正在翻译 这种方法应用于临床。尽管疫苗具有显著的治疗作用 对广泛播散、自发转移的大负担的疗效 癌症，一些小鼠是无反应的，尽管另一些小鼠的存活时间是 显著延长后，大多数小鼠仍会死亡。当我们调整疫苗以适应 临床上，继续开发新的治疗方法是非常必要的 创新的动物模型，这样我们就可以不断输入改进的策略 为翻译研究干杯。进一步的发展取决于理解 疫苗刺激免疫的潜在机制。研究， 因此，还重点研究了抗原呈递的基本方面 通过疫苗。为了进一步改进疫苗并在小鼠身上进行测试， 将解决以下治疗和机制问题：1)是否 基于MHC类IL的疫苗保护极高风险小鼠不发育乳房 癌症？2)转录调控元件的表达能否下调 并将MHC II+II+DM+肿瘤细胞转化为疫苗？3)如何 基于细胞的疫苗是否内源性地呈现MHC 11类限制性？ 人工合成的肿瘤抗原？4)疫苗细胞在 诱导抗肿瘤免疫？哪些效应细胞、细胞因子和 在治疗过程中诱导趋化因子？5)肿瘤负担与 肿瘤诱导的免疫抑制？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?