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首页> 外文期刊>The Journal of Experomental Medicine >An Expanded Peripheral T Cell Population to a Cytotoxic T Lymphocyte (Ctl)-Defined, Melanocyte-Specific Antigen in Metastatic Melanoma Patients Impacts on Generation of Peptide-Specific Ctls but Does Not Overcome Tumor Escape from Immune Surveillance in Metastatic Lesions
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An Expanded Peripheral T Cell Population to a Cytotoxic T Lymphocyte (Ctl)-Defined, Melanocyte-Specific Antigen in Metastatic Melanoma Patients Impacts on Generation of Peptide-Specific Ctls but Does Not Overcome Tumor Escape from Immune Surveillance in Metastatic Lesions

机译：转移性黑素瘤患者中的细胞毒性T淋巴细胞（Ctl）定义的黑素细胞特异性抗原的扩展外周T细胞群体对多肽特异性Ctl的产生有影响，但不能克服转移性病变的免疫监测中的肿瘤逃逸。

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It is not known if immune response to T cell–defined human histocompatibility leukocyte antigen (HLA) class I–restricted melanoma antigens leads to an expanded peripheral pool of T cells in all patients, affects cytotoxic T lymphocyte (CTL) generation, and correlates with anti-tumor response in metastatic lesions. To this end, a limiting dilution analysis technique was developed that allowed us to evaluate the same frequency of peptide-specific T cells as by staining T cells with HLA–peptide tetrameric complexes. In four out of nine patients, Melan-A/Mart-127–35–specific CTL precursors (CTLp) were ≥1/2,000 peripheral blood lymphocytes and found mostly or only in the CD45RO+ memory T cell subset. In the remaining five patients, a low (1/40,000) peptide-specific CTLp frequency was measured, and the precursors were only in the CD45RA+ naive T cell subset. Evaluation of CTL effector frequency after bulk culture indicated that peptide-specific CTLs could be activated in all patients by using professional antigen-presenting cells as dendritic cells, but CTLp frequency determined the kinetics of generation of specificity and the final number of effectors as evaluated by both limiting dilution analysis and staining with HLA-A*0201–Melan-A/Mart-1 tetrameric complexes. Immunohistochemical analysis of 26 neoplastic lesions from the nine patients indicated absence of tumor regression in most instances, even in patients with an expanded peripheral T cell pool to Melan-A/Mart-1 and whose neoplastic lesions contained a high frequency of tetramer-positive Melan-A/Mart-1–specific T cells. Furthermore, frequent lack of a “brisk” or “nonbrisk” CD3+CD8+ T cell infiltrate or reduced/absent Melan-A/Mart-1 expression in several lesions and lack of HLA class I antigens were found in some instances. Thus, expansion of peripheral immune repertoire to Melan-A/Mart-1 takes place in some metastatic patients and leads to enhanced CTL induction after antigen-presenting cell–mediated selection, but, in most metastatic lesions, it does not overcome tumor escape from immune surveillance.
机译：目前尚不清楚是否对所有定义为T细胞的人类组织相容性白细胞抗原（HLA）I类限制性黑素瘤抗原产生免疫反应，从而导致所有患者的T细胞外周血池扩大，影响细胞毒性T淋巴细胞（CTL）生成并与转移性病变中的抗肿瘤反应。为此，开发了一种有限的稀释分析技术，该技术使我们能够评估与用HLA-肽四聚体复合物染色T细胞相同的肽特异性T细胞频率。在九分之四的患者中，Melan-A / Mart-127-35特异性CTL前体（CTLp）≥1/ 2,000外周血淋巴细胞，大部分或仅在CD45RO +记忆T细胞亚群中发现。在其余五名患者中，测得的肽特异性CTLp频率较低（<1 / 40,000），并且前体仅存在于CD45RA +幼稚T细胞亚群中。大量培养后对CTL效应子频率的评估表明，通过使用专业的抗原呈递细胞作为树突状细胞，所有患者均可激活肽特异性CTL，但CTLp频率决定了特异性产生的动力学和效应子的最终数目，通过有限稀释分析和HLA-A * 0201-Melan-A / Mart-1四聚体复合物染色。对9例患者的26例肿瘤性病变的免疫组织化学分析表明，在大多数情况下，即使在外周T细胞池扩展至Melan-A / Mart-1且其肿瘤性病变包含高频率四聚体阳性Melan的患者中，也没有肿瘤消退-A / Mart-1特异性T细胞。此外，在某些情况下，发现在一些病变中经常缺乏“轻度的”或“轻度的” CD3 + CD8 + T细胞浸润或Melan-A / Mart-1表达降低/缺失/缺乏HLA I类抗原。因此，在一些转移性患者中，外周免疫成分扩展至Melan-A / Mart-1，并在抗原呈递细胞介导的选择后导致增强的CTL诱导，但是，在大多数转移性病变中，它不能克服肿瘤从免疫监视。

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