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35605191
NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness.

Blood, 2022/11/24;140(21):2261-2275.

Wilkens AB[1, 2], Fulton EC[1], Pont MJ[1], Cole GO[1], Leung I[1], Stull SM[1], Hart MR[1], Bernstein ID[1], Furlan SN[1], Riddell SR[1, 2]

Affiliations

PMID: 35605191DOI: 10.1182/blood.2021015144

Impact factor: 25.476

Abstract
Adoptive transfer of T cells expressing chimeric antigen receptors (CAR-T) effectively treats refractory hematologic malignancies in a subset of patients but can be limited by poor T-cell expansion and persistence in vivo. Less differentiated T-cell states correlate with the capacity of CAR-T to proliferate and mediate antitumor responses, and interventions that limit tumor-specific T-cell differentiation during ex vivo manufacturing enhance efficacy. NOTCH signaling is involved in fate decisions across diverse cell lineages and in memory CD8+ T cells was reported to upregulate the transcription factor FOXM1, attenuate differentiation, and enhance proliferation and antitumor efficacy in vivo. Here, we used a cell-free culture system to provide an agonistic NOTCH1 signal during naïve CD4+ T-cell activation and CAR-T production and studied the effects on differentiation, transcription factor expression, cytokine production, and responses to tumor. NOTCH1 agonism efficiently induced a stem cell memory phenotype in CAR-T derived from naïve but not memory CD4+ T cells and upregulated expression of AhR and c-MAF, driving heightened production of interleukin-22, interleukin-10, and granzyme B. NOTCH1-agonized CD4+ CAR-T demonstrated enhanced antigen responsiveness and proliferated to strikingly higher frequencies in mice bearing human lymphoma xenografts. NOTCH1-agonized CD4+ CAR-T also provided superior help to cotransferred CD8+ CAR-T, driving improved expansion and curative antitumor responses in vivo at low CAR-T doses. Our data expand the mechanisms by which NOTCH can shape CD4+ T-cell behavior and demonstrate that activating NOTCH1 signaling during genetic modification ex vivo is a potential strategy for enhancing the function of T cells engineered with tumor-targeting receptors.
MeSH terms
Humans; Mice; Animals; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; CD4-Positive T-Lymphocytes; Transcription Factors; Lymphoma; Receptors, Antigen, T-Cell; Receptor, Notch1
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