TY - JOUR
T1 - NFKBIE mutations are selected by the tumor microenvironment and contribute to immune escape in chronic lymphocytic leukemia
AU - Bonato, Alice
AU - Chakraborty, Supriya
AU - Bomben, Riccardo
AU - Canarutto, Giulia
AU - Felician, Giulia
AU - Martines, Claudio
AU - Zucchetto, Antonella
AU - Pozzo, Federico
AU - Vujovikj, Marija
AU - Polesel, Jerry
AU - Chiarenza, Annalisa
AU - Del Principe, Maria Ilaria
AU - Del Poeta, Giovanni
AU - D’Arena, Giovanni
AU - Marasca, Roberto
AU - Tafuri, Agostino
AU - Laurenti, Luca
AU - Piazza, Silvano
AU - Dimovski, Aleksandar J.
AU - Gattei, Valter
AU - Efremov, Dimitar G.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - Tumor Microenvironment
KW - Tumor Microenvironment
UR - http://hdl.handle.net/10807/302301
U2 - 10.1038/s41375-024-02224-8
DO - 10.1038/s41375-024-02224-8
M3 - Article
SN - 1476-5551
VL - 38
SP - 1511
EP - 1521
JO - Leukemia
JF - Leukemia
ER -