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Immunotherapy of CT26 murine tumors is characterized by an oligoclonal response of tissue-resident memory T cells against the AH1 rejection antigen.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-05-29 , DOI: 10.1002/eji.201948433 Marco Stringhini 1 , Philipp Probst 1 , Dario Neri 1
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-05-29 , DOI: 10.1002/eji.201948433 Marco Stringhini 1 , Philipp Probst 1 , Dario Neri 1
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Mice bearing CT26 tumors can be cured by administration of L19‐mIL12 or F8‐mTNF, two antibody fusion proteins which selectively deliver their cytokine payload to the tumor. In both settings, cancer cures crucially depended on CD8+ T cells and the AH1 peptide (derived from the gp70 protein of the murine leukemia virus) acted as the main tumor‐rejection antigen, with ∼50% of CD8+ T cells in the neoplastic mass being AH1‐specific after therapy. In order to characterize the clonality of the T cell response, its phenotype, and activation status, we isolated CD8+ T cells from tumors and secondary lymphoid organs and submitted them to T cell receptor (TCR) and total mRNA sequencing. We found an extremely diverse repertoire of more than 40 000 unique TCR sequences, but the ten most abundant TCRs accounted for >60% of CD8+ T‐cell clones in the tumor. AH1‐specific TCRs were consistently found among the most abundant sequences. AH1‐specific T cells in the tumor had a tissue‐resident memory phenotype. Treatment with L19‐mIL12 led to overexpression of IL‐12 receptor and of markers of cell activation and proliferation. These data suggest that the antitumor response driven by antibody‐cytokine fusions proceeds through an oligoclonal expansion and activation of tumor‐infiltrating CD8+ T cells.
中文翻译：
CT26鼠肿瘤的免疫疗法的特征在于组织驻留记忆T细胞针对AH1排斥抗原的寡克隆反应。
携带CT26肿瘤的小鼠可以通过施用L19-mIL12或F8-mTNF来治愈，这两种抗体融合蛋白可选择性地将其细胞因子有效载荷递送至肿瘤。在这两种情况下，癌症的治愈都非常依赖于CD8 + T细胞，而AH1肽（源自鼠白血病病毒的gp70蛋白）是主要的肿瘤排斥抗原，在肿瘤中约有50％的CD8 + T细胞治疗后肿块是AH1特异性的。为了表征T细胞反应的克隆性，其表型和激活状态，我们分离了CD8 +来自肿瘤和继发性淋巴器官的T细胞，并将其提交给T细胞受体（TCR）和总mRNA测序。我们发现了4万多个独特的TCR序列的多样性非常丰富，但是十个最丰富的TCR占肿瘤中CD8 + T细胞克隆的> 60％。在最丰富的序列中始终发现AH1特异性TCR。肿瘤中AH1特异性T细胞具有组织驻留记忆表型。用L19-mIL12进行治疗会导致IL-12受体的过度表达以及细胞活化和增殖的标志物。这些数据表明，抗体-细胞因子融合驱动的抗肿瘤反应通过寡克隆扩增和肿瘤浸润性CD8 + T细胞的活化而进行。
更新日期：2020-05-29
中文翻译：
CT26鼠肿瘤的免疫疗法的特征在于组织驻留记忆T细胞针对AH1排斥抗原的寡克隆反应。
携带CT26肿瘤的小鼠可以通过施用L19-mIL12或F8-mTNF来治愈，这两种抗体融合蛋白可选择性地将其细胞因子有效载荷递送至肿瘤。在这两种情况下，癌症的治愈都非常依赖于CD8 + T细胞，而AH1肽（源自鼠白血病病毒的gp70蛋白）是主要的肿瘤排斥抗原，在肿瘤中约有50％的CD8 + T细胞治疗后肿块是AH1特异性的。为了表征T细胞反应的克隆性，其表型和激活状态，我们分离了CD8 +来自肿瘤和继发性淋巴器官的T细胞，并将其提交给T细胞受体（TCR）和总mRNA测序。我们发现了4万多个独特的TCR序列的多样性非常丰富，但是十个最丰富的TCR占肿瘤中CD8 + T细胞克隆的> 60％。在最丰富的序列中始终发现AH1特异性TCR。肿瘤中AH1特异性T细胞具有组织驻留记忆表型。用L19-mIL12进行治疗会导致IL-12受体的过度表达以及细胞活化和增殖的标志物。这些数据表明，抗体-细胞因子融合驱动的抗肿瘤反应通过寡克隆扩增和肿瘤浸润性CD8 + T细胞的活化而进行。
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