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

(1)人体样本的研究利用食管癌患者的肿瘤样本，我们发现癌细胞中MHC I类的下调与癌组织中CD8^+ T细胞的浸润呈负相关，而CD8^+ T细胞在癌组织中的浸润与患者预后良好呈正相关。这些数据提示CD8^+ t细胞在食管癌免疫监视中发挥重要作用，MHC I类下调可能是食管癌细胞逃避免疫监视的机制之一。通过对157例肺癌样本的分析，我们发现CDC和CD8^+ T细胞在肿瘤组织中的浸润与患者良好的预后相关。此外，晚期肺癌患者肿瘤中MAGE-A4的表达预示着较短的生存期（Int J oncology, 2006）。我们对T细胞进行工程改造，使其表达由T细胞内受体和CEA抗体组成的嵌合受体。这些基因工程细胞被发现能够有效地根除表达cea的自体结肠癌细胞（cancer Sci, 2006）。我们发现混杂肽可以被NY-ESO-1特异性CD4^+ T细胞识别（癌症科学，2006）。我们发现CLUAP1是骨肉瘤相关的肿瘤抗原（国际肿瘤学杂志，2007）。(2)小鼠模型的研究我们发现抗原提呈细胞和I型辅助性T细胞之间的相互作用在抗肿瘤免疫应答中的重要性（Cancer Res, 2006）。我们还发现I型干扰素在具有toll样受体配体CpG的癌症疫苗中发挥重要作用（Int Immunol, 2006）。利用肿瘤抗原特异性TCR转基因小鼠系统，我们发现与调节性T细胞（Treg）增加相关的肿瘤进展限制了肿瘤特异性CD8^+ T细胞过继细胞治疗的效果。通过共刺激受体GITR刺激可以降低Treg，甚至在肿瘤进展的宿主中诱导有效的T细胞治疗（SFCI 2007, CRI symposium in NY 2007, JCA 2007, JSI 2007）。这些结果表明，刺激GITR等共刺激受体可能是抑制肿瘤逃避免疫监视机制的有效策略，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