Advertisement

Murine pre–B-cell ALL induces T-cell dysfunction not fully reversed by introduction of a chimeric antigen receptor

Haiying Qin, Kazusa Ishii, Sang Nguyen, Paul P. Su, Chad R. Burk, Bong-Hyun Kim, Brynn B. Duncan, Samikasha Tarun, Nirali N. Shah, M. Eric Kohler and Terry J. Fry

Key Points

  • Pre–B-cell ALL induces T-cell dysfunction in vivo, mediated in part by a non–T-cell receptor–linked mechanism.

  • Prior exposure of T cells to pre–B-cell ALL in vivo impairs subsequent functionality of CAR-expressing T cells.

Abstract

Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CARTs) has demonstrated dramatic success in relapsed/refractory pre–B-cell acute lymphoblastic leukemia (ALL), but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T-cell function, but this has not been well studied in ALL and in the context of chimeric antigen receptor (CAR) expression. Using TCF3/PBX1 and MLL-AF4–driven murine ALL models, we assessed the impact of progressive ALL on T-cell function in vivo. Vaccines protect against TCF3/PBX1.3 but were ineffective when administered after leukemia injection, suggesting immunosuppression induced early during ALL progression. T cells from leukemia-bearing mice exhibited increased expression of inhibitory receptors, including PD1, Tim3, and LAG3, and were dysfunctional following adoptive transfer in a model of T-cell receptor (TCR)–dependent leukemia clearance. Although expression of inhibitory receptors has been linked to TCR signaling, pre–B-cell ALL induced inhibitory receptor expression, at least in part, in a TCR-independent manner. Finally, introduction of a CAR into T cells generated from leukemia-bearing mice failed to fully reverse poor in vivo function.

  • Submitted December 4, 2017.
  • Accepted August 25, 2018.
View Full Text