Cancer Discov. 2020 Jan 30. pii: CD-19-0813. doi: 10.1158/2159-8290.CD-19-0813. [Epub ahead of print]

Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T cell dysfunction.

Singh N¹, Lee YG², Shestova O², Ravikumar P³, Hayer KE⁴, Hong SJ², Lu XM², Pajarillo R⁵, Agarwal S⁶, Kuramitsu S⁷, Orlando EJ⁸, Mueller KT⁹, Good CR², Berger SL, Shalem O¹⁰, Weitzman MD¹¹, Frey NV², Maude SL¹², Grupp SA¹², June CH¹³, Gill S¹⁴, Ruella M¹⁵.

Author information

1: University of Pennsylvania nathan.singh@wustl.edu.
2: University of Pennsylvania.
3: Center for cellular Immunotherapies, University of Pennsylvania.
4: Biomedical and Health Informatics, Children's Hospital of Philadelphia.
5: Center for Cellular Immunotherapies (CCI), University of Pennsylvania.
6: Center for cellular immunotherapies, University of Pennsylvania.
7: Center for Cellular Immunotherapies, University of Pennsylvania.
8: Novartis.
9: PK Sciences, Novartis Institutes for BioMedical Research.
10: Children's Hospital of Philadelphia.
11: Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia.
12: Division of Oncology, Children's Hospital of Philadelphia.
13: Parker Institute for Cancer Immunotherapy, University of Pennsylvania.
14: Division of Hematology-Oncology and Center for Cellular Immunotherapies, University of Pennsylvania.
15: Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania.

Abstract

Primary resistance to CD19-directed chimeric antigen receptor T cell therapy (CART19) occurs in 10-20% 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 which 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.