Loss-of-function mutations in NFKBIE, which encodes for the NF-κB inhibitor IκBε, are frequent in chronic lymphocytic leukemia (CLL) and certain other B-cell malignancies and have been associated with accelerated disease progression and inferior responses to chemotherapy. Using in vitro and in vivo murine models and primary patient samples, we now show that NFKBIE-mutated CLL cells are selected by microenvironmental signals that activate the NF-κB pathway and induce alterations within the tumor microenvironment that can allow for immune escape, including expansion of CD8+ T-cells with an exhausted phenotype and increased PD-L1 expression on the malignant B-cells. Consistent with the latter observations, we find increased expression of exhaustion markers on T-cells from patients with NFKBIE-mutated CLL. In addition, we show that NFKBIE-mutated murine CLL cells display selective resistance to ibrutinib and report inferior outcomes to ibrutinib treatment in NFKBIE-mutated CLL patients. These findings suggest that NFKBIE mutations can contribute to CLL progression through multiple mechanisms, including a bidirectional crosstalk with the microenvironment and reduced sensitivity to BTK inhibitor treatment.

编码 NF-κB 抑制剂 IκBε 的 NFKBIE 的功能丧失突变在慢性淋巴细胞白血病 (CLL) 和某些其他 B 细胞恶性肿瘤中很常见，并且与疾病进展加速和化疗反应较差有关。利用体外和体内小鼠模型以及主要患者样本，我们现在表明，NFKBIE 突变的 CLL 细胞是通过微环境信号选择的，这些信号激活 NF-κB 通路并诱导肿瘤微环境内的改变，从而允许免疫逃逸，包括扩增CD8+ T 细胞具有耗尽的表型，并且恶性 B 细胞上的 PD-L1 表达增加。与后面的观察结果一致，我们发现 NFKBIE 突变 CLL 患者的 T 细胞上衰竭标记物的表达增加。此外，我们还发现，NFKBIE 突变的小鼠 CLL 细胞对依鲁替尼表现出选择性耐药性，并且在 NFKBIE 突变的 CLL 患者中，依鲁替尼治疗的结果较差。这些发现表明 NFKBIE 突变可通过多种机制促进 CLL 进展，包括与微环境的双向串扰以及对 BTK 抑制剂治疗的敏感性降低。