title: Combating rituximab resistance by inducing ceramide/lysosome-involved cell death through initiation of CD20-TNFR1 co-localization.
abstract: Despite the success of CD20 antibody rituximab in immunotherapy, acquired resistance is one of the prime obstacles for the successful treatment of B-cell malignancies. There is an urgent need to intensify efforts against resistance in cancer treatment. Growing evidence indicated that lysosomes may form an "Achilles heel" for cancer cells by sensitizing them to death pathways. Here, we uncover an important role of CD20 in initiation of ceramide/lysosomal membrane permeabilization (LMP)-mediated cell death, showing that colocalization of CD20-TNFR1 after type II CD20 antibody ligation can stimulate de novo ceramide synthesis by ceramide synthase and consequently induce remarkable lysosomal permeabilization (LMP) and lysosome-mediated cell death. Further studies show that the potent lysosome-mediated cell death induced by CD20 antibodies exhibits a profound killing effect against both rituximab-sensitive and -resistant (RR) lymphoma. Furthermore, engineering of rituximab by introducing a point mutation endows it with the ability to induce potent ceramide/LMP-mediated cell death in both RR lymphoma and primary B-cell malignancies from patients with rituximab-refractory, suggesting the potential clinical application to combat rituximab resistance.
authors.affiliation: Department of Oncology, PLA General Hospital Cancer Center, PLA School of Medicine and Key Laboratory of Cell Engineering & Antibody, Beijing and Institute for Translational Medicine, Second Military Medical University , Shanghai, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Oncology, PLA General Hospital Cancer Center, PLA School of Medicine and Key Laboratory of Cell Engineering & Antibody, Beijing and Institute for Translational Medicine, Second Military Medical University , Shanghai, People's Republic of China.
authors.forename: Junlan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Oncology, PLA General Hospital Cancer Center, PLA School of Medicine and Key Laboratory of Cell Engineering & Antibody, Beijing and Institute for Translational Medicine, Second Military Medical University , Shanghai, People's Republic of China.
authors.forename: Huafei
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Nephrology, General Hospital of Jinan Military Command , Jinan, People's Republic of China.
authors.forename: Moyan
authors.initials: M
authors.lastname: Liu
authors.affiliation: Nursing Department, PLA General Hospital, PLA School of Medicine , Beijing, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Medical Department, General Hospital of Jinan Military Command , Jinan, China.
authors.forename: Lichao
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Oncology, PLA General Hospital Cancer Center, PLA School of Medicine and Key Laboratory of Cell Engineering & Antibody, Beijing and Institute for Translational Medicine, Second Military Medical University , Shanghai, People's Republic of China.
authors.forename: Lingxiong
authors.initials: L
authors.lastname: Wang
authors.affiliation: National Clinical Research Center for Normal Aging and Geriatric & Institute of Geriatric, PLA General Hospital and The Key Lab of Normal Aging and Geriatric , Beijing, People's Republic of China.
authors.forename: RuiXia
authors.initials: R
authors.lastname: LingHu
authors.affiliation: Department of Pharmacy, General Hospital of Shenyang Military Command , Shenyang, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Feng
authors.affiliation: Department of Gastroenterology, PLA 302 Hospital , Beijing, People's Republic of China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Physics, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education) , and Key Laboratory of Surface Physics, Fudan University , Shanghai, People's Republic of China.
authors.forename: Biqin
authors.initials: B
authors.lastname: Dong
authors.affiliation: Department of Physics, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education) , and Key Laboratory of Surface Physics, Fudan University , Shanghai, People's Republic of China.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Physics, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education) , and Key Laboratory of Surface Physics, Fudan University , Shanghai, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zi
authors.affiliation: Department of Lymphoma, Affiliated Hospital of Academy of Military Medical Science , Beijing, People's Republic of China.
authors.forename: Weijing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Oncology, PLA General Hospital Cancer Center, PLA School of Medicine and Key Laboratory of Cell Engineering & Antibody, Beijing and Institute for Translational Medicine, Second Military Medical University , Shanghai, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.affiliation: National Clinical Research Center for Normal Aging and Geriatric & Institute of Geriatric, PLA General Hospital and The Key Lab of Normal Aging and Geriatric , Beijing, People's Republic of China.
authors.forename: Jingkun
authors.initials: J
authors.lastname: Pan
authors.affiliation: National Clinical Research Center for Normal Aging and Geriatric & Institute of Geriatric, PLA General Hospital and The Key Lab of Normal Aging and Geriatric , Beijing, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.affiliation: National Clinical Research Center for Normal Aging and Geriatric & Institute of Geriatric, PLA General Hospital and The Key Lab of Normal Aging and Geriatric , Beijing, People's Republic of China.
authors.forename: Yazuo
authors.initials: Y
authors.lastname: Hu
authors.affiliation: National Clinical Research Center for Normal Aging and Geriatric & Institute of Geriatric, PLA General Hospital and The Key Lab of Normal Aging and Geriatric , Beijing, People's Republic of China.
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Han
authors.affiliation: National Clinical Research Center for Normal Aging and Geriatric & Institute of Geriatric, PLA General Hospital and The Key Lab of Normal Aging and Geriatric , Beijing, People's Republic of China.
authors.forename: Honghong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: National Clinical Research Center for Normal Aging and Geriatric & Institute of Geriatric, PLA General Hospital and The Key Lab of Normal Aging and Geriatric , Beijing, People's Republic of China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Oncology, PLA General Hospital Cancer Center, PLA School of Medicine and Key Laboratory of Cell Engineering & Antibody, Beijing and Institute for Translational Medicine, Second Military Medical University, Shanghai, People's Republic of China; National Clinical Research Center for Normal Aging and Geriatric & Institute of Geriatric, PLA General Hospital and The Key Lab of Normal Aging and Geriatric, Beijing, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
keywords: B-cell lymphoma; CD20 antibody; cell death; rituximab resistance; rituximab variant