Analysis of cancer immunceditine in antigen presentation-related molecules and development of treatment to inhibit escape mechanisms of cancer

(1)人体标本的研究利用食道癌患者的肿瘤标本，我们发现癌细胞中MHC-I类分子的表达下调与癌组织中CD8~+T细胞的浸润呈负相关，CD8~+T细胞在癌组织中的浸润与患者的预后呈正相关。提示CD8~+T细胞在食管癌免疫监视中起重要作用，MHC-I类分子的下调可能是食管癌细胞逃避免疫监视的一种机制。通过对157例肺癌标本的分析，我们发现CDC和CD8~+T细胞在肿瘤组织中的浸润与患者的预后密切相关。此外，晚期肺癌患者肿瘤中MAGE-A4的表达预示着短生存期(Int J Onol，2006)。我们通过基因工程使T细胞表达由T细胞受体的细胞内部分和抗CEA…抗体组成的嵌合受体更多。这些基因工程细胞被发现能够有效地清除表达CEA的自体结肠癌细胞(癌症科学，2006)。我们发现了NY-ESO-1特异性CD4^+T细胞可以识别的杂交肽(癌症科学，2006)。我们鉴定了CLUAP1是骨肉瘤相关肿瘤抗原(Int J Onol，2007)。(2)小鼠模型研究我们发现抗原提呈细胞和I型辅助T细胞之间的相互作用在抗肿瘤免疫反应中的重要性(癌症Res，2006)。我们还发现了I型干扰素在Toll样受体配体CpG癌症疫苗中的重要作用(Int免疫学，2006)。利用肿瘤抗原特异性TCR转基因小鼠系统，我们发现肿瘤进展与调节性T细胞(Treg)增加相关，限制了肿瘤特异性CD8^+T细胞过继细胞治疗的疗效。通过共刺激受体GITR的刺激减少了Treg，甚至在患有进展性肿瘤的宿主中也诱导了有效的T细胞治疗(SFCI 2007,2007年纽约CRI研讨会，JCA 2007，JSI 2007)。这些结果表明，刺激GITR等共刺激受体的操作可能是一种有效的策略，以抑制肿瘤逃避免疫监视的机制，从而导致有效的免疫治疗

(1) Research on human samplesUsing tumor samples from esophageal cancer patients, we found that down-regulation of MHC class I in cancer cells negatively correlated with the infiltration of CD8^+ T cells in cancer tissues and infiltration of CD8^+ T cells in cancer tissues positively correlated with favorable patients' prognosis. These data suggest that CD8^+ T. cells play an important role in immunosurveillance against esophageal cancer and down-regulation of MHC class I can be a mechanism that esophageal cancer cells utilize to escape from immunosurveillance (manuscript in communication).By analyzing 157 lung cancer samples, we found that infiltration of both CDC and CD8^+ T cells in tumor tissue correlated with favorable patients' prognosis. Moreover, tumor expression of MAGE-A4 in advanced lung cancer patients predicted short survival(Int J Oncol, 2006).We engineered T cells to express a chimeric receptor consists of intracellular portion of T cell receptor and antibody against CEA … More . These genetically engineered cells were found to eradicate CEA-expressing autologous colon cancer cells efficiently(Cancer Sci, 2006).We identified promiscuous peptides that can be recognized by NY-ESO-1 specific CD4^+ T cells(Cancer Sci, 2006).We identified CLUAP1 as an Osteosarcoma-related tumor antigen(Int J Oncol, 2007).(2) Research on mouse modelsWe found an importance of the interaction between antigen presenting cells and type I helper T cells in anti-tumor immune responses(Cancer Res, 2006). We also found an important role of type I interferon in cancer vaccine with a toll-like receptor ligand CpG(Int Immunol, 2006).Utilizing tumor antigen-specific TCR transgenic mouse system, we found that tumor progression associated with increased regulatory T cells(Treg) limits the efficacy of adoptive cell therapy with tumor-specific CD8^+ T cells. Stimulation through co-stimulatory receptor GITR reduced Treg and induced effective T cell therapy even in the hosts with progressing tumors(SFCI 2007, CRI symposium in NY 2007, JCA 2007, JSI 2007). These results suggest that the maneuvers to stimulate co-stimulatory receptors such as GITR can be an efficient strategy to inhibit the mechanism of tumor to escape from immunosurveillance leading to an effective immunotherapy Less