Interaction of malignancies with tissue-specific immune cells has gained interest for prognosis and intervention of emerging immunotherapies. We analyzed bone marrow T cells (bmT) as tumor-infiltrating lymphocytes in pediatric precursor-B cell acute lymphoblastic leukemia (ALL). Based on data from 100 patients, we show that ALL is associated with late-stage CD4⁺ phenotype and loss of early CD8⁺ T cells. The inhibitory exhaustion marker TIM-3 on CD4⁺ bmT increased relapse risk (RFS = 94.6/70.3%) confirmed by multivariate analysis. The hazard ratio of TIM-3 expression nearly reached the hazard ratio of MRD (7.1 vs. 8.0) indicating that patients with a high frequency of TIM-3⁺CD4⁺ bone marrow T cells at initial diagnosis have a 7.1-fold increased risk to develop ALL relapse. Comparison of wild type primary T cells to CRISPR/Cas9-mediated TIM-3 knockout and TIM-3 overexpression confirmed the negative effect of TIM-3 on T cell responses against ALL. TIM-3⁺CD4⁺ bmT are increased in ALL overexpressing CD200, that leads to dysfunctional antileukemic T cell responses. In conclusion, TIM-3-mediated interaction between bmT and leukemia cells is shown as a strong risk factor for relapse in pediatric B-lineage ALL. CD200/TIM-3-signaling, rather than PD-1/PD-L1, is uncovered as a mechanism of T cell dysfunction in ALL with major implication for future immunotherapies.

恶性肿瘤与组织特异性免疫细胞的相互作用已引起人们对新兴免疫疗法的预后和干预的兴趣。我们将骨髓 T 细胞 (bmT) 作为小儿前体 B 细胞急性淋巴细胞白血病 (ALL) 中的肿瘤浸润淋巴细胞进行了分析。基于来自 100 名患者的数据，我们表明 ALL 与晚期 CD4 ^{+表型和早期 CD8 +} T 细胞的丧失有关。多变量分析证实， CD4 ⁺ bmT上的抑制性衰竭标记 TIM-3增加了复发风险 (RFS = 94.6/70.3%)。^{TIM-3 表达的风险比几乎达到 MRD 的风险比（7.1 vs. 8.0），表明 TIM-3 +} CD4 ⁺高频率的患者初始诊断时的骨髓 T 细胞发生 ALL 复发的风险增加了 7.1 倍。野生型原代 T 细胞与 CRISPR/Cas9 介导的 TIM-3 敲除和 TIM-3 过表达的比较证实了 TIM-3 对 T 细胞对 ALL 的反应的负面影响。TIM-3 ⁺ CD4 ⁺ bmT 在过表达 CD200 的 ALL 中增加，这导致功能失调的抗白血病 T 细胞反应。总之，TIM-3 介导的 bmT 和白血病细胞之间的相互作用被证明是儿童 B 系 ALL 复发的一个强风险因素。CD200/TIM-3 信号传导，而不是 PD-1/PD-L1，被发现是 ALL 中 T 细胞功能障碍的一种机制，对未来的免疫疗法具有重要意义。