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Abstract：
We have recently described that DNA-damage inducing drug DTIC, administered before peptide (Melan-A and gp100)-vaccination, improves anti-tumor CD8+ Melan-A-specific T-cell functionality, enlarges the Melan-A+ TCR repertoire and impacts the overall survival of melanoma patients. To identify whether the two Ags employed in the vaccination differently shape the anti-tumor response, herein we have carried out a detailed analysis of phenotype, anti-tumor functionality and TCR repertoire in treatment-driven gp100-specific CD8+ T cells, in the same patients previously analyzed for Melan-A. We found that T-cell clones isolated from patients treated with vaccination alone possessed an Early/intermediate differentiated phenotype, whereas T cells isolated after DTIC plus vaccination were late-differentiated. Sequencing analysis of the TCRBV chains of 29 treatment-driven gp100-specific CD8+ T-cell clones revealed an oligoclonal TCR repertoire irrespective of the treatment schedule. The high anti-tumor activity observed in T cells isolated after chemo-immunotherapy was associated with low PD-1 expression. Differently, T-cell clones isolated after peptide-vaccination alone expressed a high level of PD-1, along with LAG-3 and TIM-3, and were neither tumor-reactive nor polyfunctional. Blockade of PD-1 reversed gp100-specific CD8+ T-cell dysfunctionality, confirming the direct role of this co-inhibitory molecule in suppressing anti-tumor activity, differently from what we have previously observed for Melan-A+CD8+ T cells, expressing PD-1 but highly functional. These findings indicate that the functional advantage induced by combined chemo-immunotherapy is determined by the tumor antigen nature, T-cell immune-checkpoints phenotype, TCR repertoire diversity and anti-tumor T-cell quality and highlights the importance of integrating these parameters to develop effective immunotherapeutic strategies.
摘要：
我们最近描述了诱导DNA损伤的药物DTIC，在肽（Melan-A和gp100）疫苗接种之前施用，改善抗肿瘤CD8+Melan-A特异性T细胞功能，扩大Melan-A+TCR库，并影响黑色素瘤患者的总体生存率。为了确定疫苗接种中使用的两种Ags是否不同地塑造抗肿瘤反应，本文对表型进行了详细分析，治疗驱动的gp100特异性CD8+T细胞中的抗肿瘤功能和TCR库，在以前分析过Melan-A的相同患者中我们发现，从单独接种疫苗的患者中分离的T细胞克隆具有早期/中等分化表型，而DTIC+疫苗接种后分离的T细胞是晚期分化的。29个处理驱动的gp100特异性CD8T细胞克隆的TCRBV链的测序分析揭示了寡克隆TCR库，而与治疗方案无关。在化学免疫疗法后分离的T细胞中观察到的高抗肿瘤活性与低PD-1表达相关。不同的是,单独肽疫苗接种后分离的T细胞克隆表达高水平的PD-1，以及LAG-3和TIM-3，既不是肿瘤反应性也不是多功能的。阻断PD-1可逆转gp100特异性CD8+T细胞功能失调，证实了这种共抑制分子在抑制抗肿瘤活性中的直接作用，与我们之前观察到的Melan-A+CD8+T细胞不同，表达PD-1，但具有很高的功能。这些发现表明，联合化学免疫疗法诱导的功能优势是由肿瘤抗原性质决定的。T细胞免疫检查点表型，TCR库多样性和抗肿瘤T细胞质量，并强调整合这些参数以开发有效的免疫治疗策略的重要性。
