TY - JOUR
T1 - Antigen glycosylation regulates efficacy of CAR T cells targeting CD19
AU - Heard, Amanda
AU - Landmann, Jack H.
AU - Hansen, Ava R.
AU - Papadopolou, Alkmini
AU - Hsu, Yu Sung
AU - Selli, Mehmet Emrah
AU - Warrington, John M.
AU - Lattin, John
AU - Chang, Jufang
AU - Ha, Helen
AU - Haug-Kroeper, Martina
AU - Doray, Balraj
AU - Gill, Saar
AU - Ruella, Marco
AU - Hayer, Katharina E.
AU - Weitzman, Matthew D.
AU - Green, Abby M.
AU - Fluhrer, Regina
AU - Singh, Nathan
N1 - Funding Information:
The authors wish to thank Ophir Shalem (The Children’s Hospital of Philadelphia) and Jonathan Schug (University of Pennsylvania) for substantial feedback in the development and execution of the genome-wide knockout screen and sequencing, Julie Ritchey, Alun Carter, and Matthew Cooper (Washington University School of Medicine) for intellectual and technical support, Peter Steinberger (Medical University of Vienna) for the Jurkat triple parameter reporter cell line and Elena Orlando (Novartis) for useful discussions. This work was supported by NIH K08CA237740 and The Amy Strelzer Manasevit Research Grant from the Be The Match Foundation (N.S.), NIH K08CA212299 (A.M.G.) as well as by the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) grants 263531414/FOR 2290 and 254872893/FL 635/2-3 (R.F.) Illustrations made using BioRender.com.
Funding Information:
The authors wish to thank Ophir Shalem (The Children’s Hospital of Philadelphia) and Jonathan Schug (University of Pennsylvania) for substantial feedback in the development and execution of the genome-wide knockout screen and sequencing, Julie Ritchey, Alun Carter, and Matthew Cooper (Washington University School of Medicine) for intellectual and technical support, Peter Steinberger (Medical University of Vienna) for the Jurkat triple parameter reporter cell line and Elena Orlando (Novartis) for useful discussions. This work was supported by NIH K08CA237740 and The Amy Strelzer Manasevit Research Grant from the Be The Match Foundation (N.S.), NIH K08CA212299 (A.M.G.) as well as by the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) grants 263531414/FOR 2290 and 254872893/FL 635/2-3 (R.F.) Illustrations made using BioRender.com.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - While chimeric antigen receptor (CAR) T cells targeting CD19 can cure a subset of patients with B cell malignancies, most patients treated will not achieve durable remission. Identification of the mechanisms leading to failure is essential to broadening the efficacy of this promising platform. Several studies have demonstrated that disruption of CD19 genes and transcripts can lead to disease relapse after initial response; however, few other tumor-intrinsic drivers of CAR T cell failure have been reported. Here we identify expression of the Golgi-resident intramembrane protease Signal peptide peptidase-like 3 (SPPL3) in malignant B cells as a potent regulator of resistance to CAR therapy. Loss of SPPL3 results in hyperglycosylation of CD19, an alteration that directly inhibits CAR T cell effector function and suppresses anti-tumor cytotoxicity. Alternatively, over-expression of SPPL3 drives loss of CD19 protein, also enabling resistance. In this pre-clinical model these findings identify post-translational modification of CD19 as a mechanism of antigen escape from CAR T cell therapy.
AB - While chimeric antigen receptor (CAR) T cells targeting CD19 can cure a subset of patients with B cell malignancies, most patients treated will not achieve durable remission. Identification of the mechanisms leading to failure is essential to broadening the efficacy of this promising platform. Several studies have demonstrated that disruption of CD19 genes and transcripts can lead to disease relapse after initial response; however, few other tumor-intrinsic drivers of CAR T cell failure have been reported. Here we identify expression of the Golgi-resident intramembrane protease Signal peptide peptidase-like 3 (SPPL3) in malignant B cells as a potent regulator of resistance to CAR therapy. Loss of SPPL3 results in hyperglycosylation of CD19, an alteration that directly inhibits CAR T cell effector function and suppresses anti-tumor cytotoxicity. Alternatively, over-expression of SPPL3 drives loss of CD19 protein, also enabling resistance. In this pre-clinical model these findings identify post-translational modification of CD19 as a mechanism of antigen escape from CAR T cell therapy.
UR - http://www.scopus.com/inward/record.url?scp=85131801925&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-31035-7
DO - 10.1038/s41467-022-31035-7
M3 - Article
C2 - 35690611
AN - SCOPUS:85131801925
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3367
ER -