Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer
Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer
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DOI：
10.1073/pnas.231326898
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发表时间：
2001-11-06
影响因子：
11.1
通讯作者：
Gaudernack, G
中科院分区：
文献类型：
--
作者：
Saeterdal, I;Bjorheim, J;Gaudernack, G
肿瘤浸润淋巴细胞 (TIL) 的功能作用和特异性通常尚不明确。显着的淋巴细胞浸润是最常见形式的遗传性结肠癌、遗传性非息肉病性结肠癌（HNPCC）和具有微卫星不稳定性（MSI）表型的相应自发性结肠癌的标志。这些癌症是由 DNA 错配修复机制的遗传性或后天性缺陷引起的。 MSI表型背后的分子机制为理解淋巴细胞反应提供了线索，它可以可靠地预测携带核苷酸重复序列（例如TGF beta RII和BAX）的候选基因中移码突变产生的潜在T细胞表位，因此这些肿瘤代表了一个有趣的人类系统，用于研究TIL和表征肿瘤特异性T细胞。我们在此描述了针对几种 T 辅助细胞表位的 T 细胞反应性，这些表位代表 TGF beta RII、TIL 和 MSI+ 肿瘤患者外周血淋巴细胞中常见的移码突变。肽 SLVRLSSCVPVALMSAMTTSSSQ 被三名自发性 MSI+ 结肠癌患者中的两名以及所有三名 HNPCC 患者的 T 细胞识别。由于此类突变存在于该患者群体中 90% 的癌症中，因此这些新表征的表位为癌症疫苗提供了有吸引力的靶标，包括针对携带 HNPCC 遗传倾向的个体的预防性疫苗。
The functional role and specificity of tumor infiltrating lymphocytes (TIL) is generally not well characterized. Prominent lymphocyte infiltration is the hallmark of the most common form of hereditary colon cancer, hereditary nonpolyposis colon cancer (HNPCC) and the corresponding spontaneous colon cancers with the microsatellite instability (MSI) phenotype. These cancers are caused by inherited or acquired defects in the DNA mismatch-repair machinery. The molecular mechanism behind the MSI phenotype provides a clue to understanding the lymphocyte reaction by allowing reliable prediction of potential T cell epitopes created by frameshift mutations in candidate genes carrying nucleotide repeat sequences, such as TGF beta RII and BAX These tumors therefore represent an interesting human system for studying TIL and characterizing tumor-specific T cells. We here describe T cell reactivity against several T helper cell epitopes, representing a common frameshift mutation in TGF beta RII, in TIL and peripheral blood lymphocytes from patients with MSI+ tumors. The peptide SLVRLSSCVPVALMSAMTTSSSQ was recognized by T cells from two of three patients with spontaneous MSI+ colon cancers and from all three patients with HNPCC. Because such mutations are present in 90% of cancers within this patient group, these newly characterized epitopes provide attractive targets for cancer vaccines, including a prophylactic vaccine for individuals carrying a genetic disposition for developing HNPCC.