Decroos Amandine, Meddour Sarah, Demoy Marine, Piccirilli Nathalie, Rousselot Philippe, Nicolini Franck E, Ragot Stéphanie, Gombert Jean-Marc, Herbelin André, Barbarin Alice, Cayssials Emilie
Université de Poitiers, Institut National de la Santé Et de la Recherche Médicale, Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation U1313, Poitiers, France.
Centre Hospitalier Universitaire de Poitiers, Délégation à la Recherche Clinique et à l'Innovation, Poitiers, France.
Front Immunol. 2024 Nov 15;15:1473139. doi: 10.3389/fimmu.2024.1473139. eCollection 2024.
Considering the general view that unconventional immune effectors play a major role in antitumor immunity, we recently postulated that the distinct new innate CD8 T-cell pool (co-expressing the transcription factor Eomesodermin and innate markers such as KIR/NKG2A) may counteract tumor cells, and thereby be potential target for cancer therapy. Here, to test this assumption, we used successfully targeted anti-leukemic therapy discontinuation (TFR) in chronic myeloid leukemia (CML). Numerical and functional status of innate CD8 T-cells, iNKT cells and γδ T-cells, in comparison with NK cells, was compared longitudinally between non-relapsed patients (i.e., with > 12 months TFR) and relapsed patients (i.e., who experienced molecular recurrence during the first 12 months after TKI cessation) in a prospective pilot cohort (n=32), starting from treatment discontinuation (D0). Perforin, a key cytotoxic immune player, was expressed in a significantly higher proportion of both innate CD8 T-cell and NK-cell subsets in non-relapsed patients, compared with relapsed patients at D0. In parallel, we assessed the expression of PD-1, an exhaustion marker used as target in cancer therapy. For all T-cell subsets, surface-expression level of PD-1 decreased in non-relapsed patients compared with relapsed patients at D0. This was particularly the case when considering iNKT cells for which surface-expression level of PD-1 even decreased relative to healthy control subjects. Lastly, we found a negative correlation between the proportion of innate CD8 T-cells expressing PD-1 and those expressing perforin in non-relapsed patients at D0. The fact that this was not the case in conventional CD8 T-cells is compatible with a reprogrammed effector profile preferentially targeting innate CD8 T-cells in non-relapsed patients. All in all, our results highlight NK cells and innate CD8 T-cells harboring cytotoxic content, as well as global downregulation of PD-1-expression on effector T-cells, as potential predictive functional signatures for successful TFR in CML. Considering innate CD8 T-cells, further investigations are needed to determine whether their possible contributory role in cancer surveillance in CML could be extended to other cancers, and also whether their targeting by immune cheek-point inhibitors could enhance their anti-tumoral functions.
考虑到非传统免疫效应器在抗肿瘤免疫中起主要作用这一普遍观点，我们最近推测，独特的新的先天性CD8 T细胞库（共表达转录因子Eomesodermin和KIR/NKG2A等先天性标志物）可能会对抗肿瘤细胞，因此可能是癌症治疗的潜在靶点。在此，为了验证这一假设，我们在慢性粒细胞白血病（CML）中成功使用了靶向抗白血病治疗停药（TFR）。在前瞻性试点队列（n = 32）中，从治疗停药（D0）开始，纵向比较了非复发患者（即TFR>12个月）和复发患者（即TKI停药后前12个月内发生分子复发的患者）中先天性CD8 T细胞、iNKT细胞和γδ T细胞与NK细胞相比的数量和功能状态。与D0时的复发患者相比，非复发患者中，关键细胞毒性免疫因子穿孔素在先天性CD8 T细胞和NK细胞亚群中的表达比例显著更高。同时，我们评估了PD-1的表达，PD-1是一种在癌症治疗中用作靶点的耗竭标志物。对于所有T细胞亚群，与D0时的复发患者相比，非复发患者中PD-1的表面表达水平降低。在考虑iNKT细胞时尤其如此，其PD-1的表面表达水平甚至相对于健康对照受试者也有所降低。最后，我们发现D0时非复发患者中表达PD-1的先天性CD8 T细胞比例与表达穿孔素的先天性CD8 T细胞比例之间呈负相关。在传统CD8 T细胞中并非如此，这与非复发患者中优先靶向先天性CD8 T细胞的重编程效应器谱相符。总而言之，我们的结果突出了具有细胞毒性成分的NK细胞和先天性CD8 T细胞，以及效应T细胞上PD-1表达的整体下调，作为CML中成功TFR的潜在预测功能特征。考虑到先天性CD8 T细胞，需要进一步研究以确定它们在CML癌症监测中的可能贡献作用是否可以扩展到其他癌症，以及免疫检查点抑制剂对它们的靶向作用是否可以增强其抗肿瘤功能。
