Rosenberger Leonie, Hansmann Leo, Anastasopoulou Vasiliki, Wolf Steven P, Drousch Kimberley, Moewes Christina, Feng Xinyi, Cao Guoshuai, Huang Jun, Yew Poh Yin, Strønen Erlend, Kato Taigo, Saligrama Naresha, Olweus Johanna, Nakamura Yusuke, Willimsky Gerald, Blankenstein Thomas, Schreiber Hans, Leisegang Matthias
Institute of Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
J Immunother Cancer. 2025 May 2;13(5):e011351. doi: 10.1136/jitc-2024-011351.
The development of T-cell receptor (TCR)-based T-cell therapies is hampered by the difficulties in identifying therapeutically effective tumor-specific TCRs from the natural repertoire of a patient's cancer-specific T cells.
Here, we mimic experimentally near-patient conditions to analyze the T-cell repertoire in euthymic tumor-bearing mice responding to the H-2K-presented neoantigen p68 (mp68). We temporarily separated the time point of mp68 expression from that of cancer cell transplantation to exclude the influence of injection-induced inflammation on T-cell priming. Thus, the mp68-specific T-cell response could only develop after the acute inflammatory phase had subsided.
We found that mp68-specific TCRs isolated from either tumor-infiltrating T cells or spleens of mice immunized with mp68-expressing cancer cells are diverse and not inherently therapeutic when introduced into peripheral T cells and used for adoptive therapy of established tumors. While measuring short-term T-cell responses in vitro was unreliable for some TCRs in predicting their therapeutic failure, assessing the persistence of cancer cell destruction by TCR-modified T cells in long-term cultures accurately predicted therapeutic outcomes. A tumor-derived TCR with optimal function was also correctly identified with this approach when analyzing human TCRs that recognize the HLA-A2-presented neoantigen CDK4.
We show that a neoantigen-directed T-cell response in tumor-bearing hosts comprises a diverse repertoire. Infiltration and expansion of certain T-cell clonotypes in the tumor do not necessarily correlate with therapeutic efficacy of their TCRs in adoptive therapy. We propose that analysis of persistent rather than immediate responses of TCR-modified T cells in vitro serves as a reliable parameter to identify TCRs that are therapeutically effective in vivo.
基于T细胞受体（TCR）的T细胞疗法的发展受到阻碍，原因在于难以从患者癌症特异性T细胞的天然库中鉴定出具有治疗效果的肿瘤特异性TCR。
在此，我们通过实验模拟接近患者的条件，以分析荷瘤正常胸腺小鼠中对H-2K呈递的新抗原p68（mp68）产生反应的T细胞库。我们将mp68表达的时间点与癌细胞移植的时间点暂时分开，以排除注射诱导的炎症对T细胞启动的影响。因此，mp68特异性T细胞反应只能在急性期炎症消退后才会发生。
我们发现，从肿瘤浸润性T细胞或用表达mp68的癌细胞免疫的小鼠脾脏中分离出的mp68特异性TCR是多样的，当引入外周T细胞并用于已建立肿瘤的过继性治疗时，它们本身并无治疗效果。虽然体外测量某些TCR的短期T细胞反应对于预测其治疗失败并不可靠，但评估经TCR修饰的T细胞在长期培养中对癌细胞破坏的持续性可准确预测治疗结果。在分析识别HLA-A2呈递的新抗原CDK4的人类TCR时，用这种方法也正确鉴定出了具有最佳功能的肿瘤衍生TCR。
我们表明，荷瘤宿主中针对新抗原的T细胞反应包含多样的TCR库。肿瘤中某些T细胞克隆型的浸润和扩增并不一定与其TCR在过继性治疗中的治疗效果相关。我们提出，体外分析经TCR修饰的T细胞的持续性而非即时反应，可作为鉴定在体内具有治疗效果的TCR的可靠参数。
