RT Journal Article
SR Electronic
T1 Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 732
OP 742
DO 10.1158/2326-6066.CIR-19-0908
VO 8
IS 6
A1 Wijewarnasuriya, Dinali
A1 Bebernitz, Christina
A1 Lopez, Andrea V.
A1 Rafiq, Sarwish
A1 Brentjens, Renier J.
YR 2020
UL http://cancerimmunolres.aacrjournals.org/content/8/6/732.abstract
AB Although clinical responses with CD19-targeting chimeric antigen receptor (CAR) T-cell treatment have been observed in patients with certain hematologic malignancies, high rates of disease relapse highlight the necessity to understand and improve mechanisms of CAR T-cell failure. Because T-cell dysfunction is thought to contribute to CAR T-cell treatment failure, understanding what mechanisms drive T cells into this dysfunctional state may aid optimal design of efficacious CAR T cells. Dysfunctional CAR T cells have been characterized as having upregulated inhibitory receptors and decreased cytolytic capabilities. Previous studies have identified a role for sustained CAR CD3ζ signaling in CAR T-cell dysfunction. Here, we demonstrate a mechanism that drives dysfunction in CAR T cells through excessive costimulation. Fully activated CD19-targeted CAR T cells were rendered dysfunctional upon stimulation with both endogenous CD28 stimulation and CAR-mediated CD28 costimulation. Costimulation-driven dysfunction of CAR T cells was demonstrated in a syngeneic immunocompetent mouse model, in which CAR T cells were activated with signals 1 (CD3ζ), 2 (CD28), and 3 (IL12). Thus, we show that CAR T-cell dysfunction can be driven through excessive CD28 and 4-1BB costimulation.See related article by Drakes et al., p. 743