Immune response and escape in human cancers

近十年来，人类肿瘤免疫治疗的研究取得了显著进展。在我们的实验室，确定了人类肿瘤抗原及其hla - a24限制性免疫原性肽表位，以开发治疗性和预防性的人类癌症疫苗。在这些多肽中，survivin 2B肽来源于survivin，一种凋亡蛋白抑制剂（IAP），在超过50%的多种肿瘤患者中具有免疫原性，包括结肠癌、胰腺癌、肺癌、乳腺癌、膀胱癌和口腔癌。目前正在进行临床试验，通过仔细的免疫学监测，我们将最终能够知道这些疫苗是否能在临床上起作用。为了制定有效的临床治疗方案，应该更彻底地研究人类肿瘤材料中的免疫肿瘤逃逸机制。为此，成功建立了抗hla - a、B、C等位基因特异性单克隆抗体EMR8-5，该抗体可用于常规石蜡包埋切片。出乎意料的是，我们的数据表明，高比例的人类癌症，特别是乳腺癌和前列腺癌，在其原发癌组织中丢失了hla - I类分子。我们将讨论解决这一重要的既老又新问题的可能性。尽管最近越来越多的证据表明热休克蛋白（HSPs）作为所谓的危险信号在启动先天免疫和随后激活获得性免疫中起着重要作用，但这一现象的确切免疫学基础仍有待阐明。我们的研究表明，某些热休克蛋白伴随的免疫原肽，特别是热休克蛋白90，可以有效地进入树突状细胞的交叉引物途径。有趣的是，这种交叉启动与tap无关，并遵循内吞途径。在HLA-A24转基因小鼠模型中，我们还发现hsp90伴随肽复合物可以作为一种潜在的肿瘤治疗疫苗。

The investigation of human tumor immunotherapy has remarkably advanced in the past decade. In our laboratory, human tumor antigens and their HLA-A24-restricted immunogenic peptide epitopes were determined to develop therapeutic and prophylactic human cancer vaccines. Among these peptides, survivin 2B peptide derived from survivin, an inhibitor of apoptosis protein (IAP), is immunogenic in more than 50 % of cancer patients with a wide variety of tumors, including colon, pancreas, lung, breast, urinary bladder and oral cancers. It is now under clinical and with careful immunological monitoring we will finally be able to know if these vaccines can work clinically.To develop a potent clinical therapeutic protocol, the immunological tumor escape mechanism should be more thoroughly examined in human tumor materials. To this end, anti-HLA-A, B, and C allele-specific monoclonal antibody EMR8-5, which can be used in routine paraffin-embedded sections, was successfully established. Unexpectedly, our data indicated that a high percentage of human cancers, particularly breast and prostate cancers, lost HLA-class I molecules in their primary cancer tissues. We will discuss possibilities for resolution of this important old but yet new problem.Although recent evidence has been accumulating for an important role of the heat shock proteins (HSPs) as so-called danger signals in initiating innate immunity and consequently activating acquired immunity, the precise immunological basis for this phenomenon remains to be elucidated. Our study indicated that certain HSP-chaperoned immunogenic peptides, particularly HSP90, could efficiently enter the cross-priming pathway in dendritic cells. Interestingly, this cross-priming was TAP-independent and followed endocytic pathways. We also showed that HSP90-chaperoned peptide complexes could work as a potential tumor therapeutic vaccine in the HLA-A24 transgenic mouse model.