Ectopic PU.1 Expression Provides Chimeric Antigen Receptor (CAR) T Cells with Innate Cell Capacities Including IFN-β Release

Author:

Harrer Dennis Christoph12,Eder Matthias2,Barden Markus2,Pan Hong2,Herr Wolfgang1,Abken Hinrich2ORCID

Affiliation:

1. Department of Hematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, Germany

2. Leibniz Institute for Immunotherapy, Division of Genetic Immunotherapy, University Regensburg, 93053 Regensburg, Germany

Abstract

Chimeric antigen receptor (CAR) T cell therapy has achieved extraordinary success in eliminating B cell malignancies; however, so far, it has shown limited efficacy in the treatment of solid tumors, which is thought to be due to insufficient CAR T cell activation. We hypothesized that the transcription factor PU.1, a master regulator of innate cell functionality, may augment pro-inflammatory CAR T cell activation. T cells were engineered with a CEA-specific CAR together with the constitutive expression of PU.1. CAR-redirected T cell activation was recorded for canonical functionality in vitro under conditions of prolonged repetitive antigen exposure. Ectopic PU.1 expression in CAR T cells upregulated the costimulatory receptors CD40, CD80, CD86, and CD70, which, unexpectedly, did not augment effector functions but hampered the upregulation of 4-1BB, decreased IL-2 production, reduced CAR T cell proliferation, and impaired their cytotoxic capacities. Under “stress” conditions of repetitive engagement of cognate tumor cells, CAR T cells with ectopic PU.1 showed reduced persistence, and finally failed to control the growth of cancer cells. Mechanistically, PU.1 caused CAR T cells to secrete IFN-β, a cytokine known to promote CAR T cell attrition and apoptosis. Collectively, PU.1 can polarize the functional capacities of CAR T cells towards innate cells.

Funder

Deutsche Forschungsgemeinschaft

Else-Kröner Fresenius Foundation

Bavarian Cancer Research Center (BZKF) BZKF-Young Scientist Fellowship

Publisher

MDPI AG

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