The response of autologous T cells to a human melanoma is dominated by mutated neoantigens
The response of autologous T cells to a human melanoma is dominated by mutated neoantigens
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DOI：
10.1073/pnas.0500090102
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发表时间：
2005-11-01
影响因子：
11.1
通讯作者：
Wölfel, T
中科院分区：
文献类型：
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作者：
Lennerz, V;Fatho, M;Wölfel, T
我们对导致抗肿瘤免疫的途径的理解可能依赖于对患者自体T细胞应答的主要抗原靶点的正确认识。在来自患者DT的黑色素瘤模型中，我们将冷冻保存的短期自体混合淋巴细胞-肿瘤细胞培养物（MLTC）与IFN-γ酶联免疫斑点（ELISPOT）测定组合用于cDNA表达筛选。我们确定了三个以前未知的肽加工黑素蛋白酪氨酸酶（由HLA-A*2601和-B*3801）和gp 100（由HLA-B*07021）和五个新抗原体细胞点突变产生的患者的黑色素瘤。这些突变存在于SIRT 2、GPNMB、SNRP 116、SNRPD 1和RBAF 600基因中。含有突变残基的肽由HLA-A*03011、-B*07021和-B*3801表示。到目前为止，SIRT 2已经证明了突变诱导的功能障碍。在从不同年份的患者外周血淋巴细胞独立扩增的MLTC应答者群体中，针对突变表位的T细胞明显占主导地位。这些结果证明了细胞抗肿瘤反应的高度个体化，并支持了对自体T细胞反应的主要靶点进行个体化监测和治疗方法的需求，这最终可能导致更有效的癌症免疫治疗。
Our understanding of pathways leading to antitumor immunity may depend on an undistorted knowledge of the primary antigenic targets of patients' autologous T cell responses. In the melanoma model derived from patient DT, we applied cryopreserved short-term autologous mixed lymphocyte-tumor cell cultures (MLTCs) in combination with an IFN-gamma enzyme-linked immunospot (ELISPOT) assay to cDNA expression screening. We identified three previously unknown peptides processed from melanosomal proteins tyrosinase (presented by HLA-A*2601 and -B*3801) and gp100 (presented by HLA-B*07021) and five neoantigens generated by somatic point mutations in the patient's melanoma. The mutations were found in the genes SIRT2, GPNMB, SNRP116, SNRPD1, and RBAF600. Peptides containing the mutated residues were presented by HLA-A*03011, -B*07021, and -B*3801. Mutation-induced functional impairment was so far demonstrated for SIRT2. Within MLTC responder populations that were independently expanded from the patient's peripheral blood lymphocytes of different years, T cells against mutated epitopes clearly predominated. These results document a high degree of individuality for the cellular antitumor response and support the need for individualizing the monitoring and therapeutic approaches to the primary targets of the autologous T cell response, which may finally lead to a more effective cancer immunotherapy.