Sentís I, Melero J L, Cebria-Xart A, Grzelak M, Soto M, Michel A, Rovira Q, Rodriguez-Hernandez C J, Caratù G, Urpi A, Sauvage C, Mendizabal-Sasieta A, Maspero D, Lavarino C E, Pascual-Reguant A, Castañeda Heredia A, Muñoz Perez J P, Mora J, Harari A, Nieto J C, Avgustinova A, Heyn H
Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Spain.
Omniscope, Barcelona, Spain.
Ann Oncol. 2025 May 20. doi: 10.1016/j.annonc.2025.05.530.
Immune checkpoint inhibition (ICI) has revolutionized oncology, offering extended survival and long-term remission in previously incurable cancers. While highly effective in tumors with high mutational burden, lowly mutated cancers, including pediatric malignancies, present low response rate and limited predictive biomarkers.
We present a framework for the identification and validation of tumor-reactive T cells as a biomarker to quantify ICI efficacy and as candidates for a personalized T-cell receptor T-cell (TCR-T) therapy. Therefore, we profiled a pediatric malignant rhabdoid tumor patient with complete remission after ICI therapy using deep single-cell T-cell receptor (TCR) repertoire sequencing of the tumor microenvironment (TME) and the peripheral blood.
Tracking T-cell dynamics longitudinally from the tumor to cells in circulation over a time course of 12 months revealed a systemic response and durable clonal expansion of tumor-resident and ICI-induced TCR clonotypes. We functionally validated tumor reactivity of TCRs identified from the TME and the blood by co-culturing patient-derived tumor cells with TCR-engineered autologous T cells. Here, we observed unexpectedly high frequencies of tumor-reactive TCR clonotypes in the TME and confirmed T-cell dynamics in the blood post-ICI to predict tumor reactivity.
These findings strongly support spatiotemporal tracking of T-cell activity in response to ICI to inform therapy efficacy and to serve as a source of tumor-reactive TCRs for personalized TCR-T designs.
免疫检查点抑制（ICI）彻底改变了肿瘤学，为既往无法治愈的癌症带来了生存期延长和长期缓解。虽然ICI在高突变负荷肿瘤中非常有效，但低突变癌症，包括儿科恶性肿瘤，反应率低且预测生物标志物有限。
我们提出了一个框架，用于识别和验证肿瘤反应性T细胞，将其作为量化ICI疗效的生物标志物以及个性化T细胞受体T细胞（TCR-T）疗法的候选物。因此，我们对一名接受ICI治疗后完全缓解的儿科恶性横纹肌肉瘤患者进行了肿瘤微环境（TME）和外周血的深度单细胞T细胞受体（TCR）库测序。
在12个月的时间过程中纵向追踪从肿瘤到循环中细胞的T细胞动态，揭示了肿瘤驻留和ICI诱导的TCR克隆型的全身反应和持久克隆扩增。我们通过将患者来源的肿瘤细胞与TCR工程化的自体T细胞共培养，在功能上验证了从TME和血液中鉴定出的TCR的肿瘤反应性。在此，我们意外地观察到TME中肿瘤反应性TCR克隆型的高频率，并证实了ICI后血液中的T细胞动态可预测肿瘤反应性。
这些发现有力地支持了对T细胞活性进行时空追踪以评估治疗疗效，并作为个性化TCR-T设计中肿瘤反应性TCR的来源。
