Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction

• Published in: Cancer discovery 2020-04, Vol.10 (4), p.552-567
• Main Authors: Singh, Nathan, Lee, Yong Gu, Shestova, Olga, Ravikumar, Pranali, Hayer, Katharina E, Hong, Seok Jae, Lu, Xueqing Maggie, Pajarillo, Raymone, Agarwal, Sangya, Kuramitsu, Shunichiro, Orlando, Elena J, Mueller, Karen Thudium, Good, Charly R, Berger, Shelley L, Shalem, Ophir, Weitzman, Matthew D, Frey, Noelle V, Maude, Shannon L, Grupp, Stephan A, June, Carl H, Gill, Saar, Ruella, Marco
• Format: Article
• Language: English
• Subjects: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Receptors, Chimeric Antigen - metabolism; Receptors, Death Domain - metabolism; Signal Transduction
• ISSN: 2159-8274; 2159-8290; 2159-8290
• DOI: 10.1158/2159-8290.CD-19-0813

Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction. SIGNIFICANCE: Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy. .