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

(1)人体样本研究利用食管癌患者的肿瘤样本，我们发现癌细胞中MHC I类分子的下调与癌组织中CD 8 ^+ T细胞的浸润呈负相关，而癌组织中CD 8 ^+ T细胞的浸润与患者的预后良好呈正相关。提示CD 8 ^+ T. CD 8 ^+ T细胞在食管癌的免疫监视中起着重要的作用，而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（通讯稿）。通过分析157例肺癌标本，我们发现肿瘤组织中CDC和CD 8 ^+ T细胞的浸润与良好的患者预后相关。此外，MAGE-A4在晚期肺癌患者中的肿瘤表达预测了较短的生存期（Int J Oncol，2006）。我们将T细胞工程化以表达由T细胞受体的细胞内部分和针对CEA的抗体组成的嵌合受体 ...更多信息 .发现这些基因工程细胞有效地根除CEA表达的自体结肠癌细胞（Cancer Sci，2006）。我们鉴定了可以被NY-ESO-1特异性CD 4 ^+ T细胞识别的混杂肽（Cancer Sci，2006）。我们鉴定了CLUAP 1作为骨肉瘤相关的肿瘤抗原（Int J Oncol，2007）。(2)对小鼠模型的研究我们发现抗原呈递细胞和I型辅助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型干扰素在带有toll样受体配体CpG的癌症疫苗中具有重要作用（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使用肿瘤特异性CD 8 ^+ T细胞的过继细胞治疗的功效。通过共刺激受体GITR的刺激减少了Treg并诱导了有效的T细胞治疗，即使在患有进展性肿瘤的宿主中也是如此（SFCI 2007，CRI symposium in NY 2007，JCA 2007，JSI 2007）。这些结果表明，刺激共刺激受体如GITR的策略可以有效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