Dataset Information

Regulatory programs of B-cell activation and germinal center reaction allow for B-ALL escape from CD19 CAR T-cell therapy

ABSTRACT: CAR T-cell therapy has led to tremendous successes in the treatment of B-cell malignancies. However, 30%-50% of treated patients relapse – often with reduced target antigen expression. We report that anti-CD19 CAR T-cells cause a rapid reduction of CD19 expression within hours in CAR-T exposed CD19+ B-ALL cells. Initially, anti-CD19 CAR T-cells cause CD19 clusters at the T-cell – leukemia cell interface followed by CD19 internalization and decreased CD19 surface expression. Subsequently, CD19 expression is repressed by transcriptional rewiring. Using single-cell RNA-seq and single-cell ATAC-seq we demonstrate that a subset of CD19low cells that are refractory to CAR T-cell killing employ transcriptional programs of physiological B-cell activation and germinal center reaction in order to sustain decreased CD19 expression. Inhibiting B-cell activation programs with the BTK inhibitor ibrutinib increased the cytotoxic efficacy of anti-CD19 CAR T-cells without effecting CAR T-cell viability. These results demonstrate transcriptional plasticity as an underlying mechanism of CAR T-resistance and highlight the importance of combining CAR T-cell therapy with targeted therapies that aim to overcome this plasticity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE176418 | GEO | 2022/06/09

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive tumor microenvironment (TME), which is densely populated and supported by protumoral glioma-associated microglia and macrophages (GAMs). Targeting CD47, a don't-eat-me signal overexpressed by tumor cells, disrupts the CD47-SIRPalpha axis and induces GAM phagocytic function. However, antibody-mediated CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. To overcome these limitations, we combined local CAR T cell therapy with paracrine GAM modulation to effectively eliminate GBM. To this end, we engineered a new CAR T cell against epidermal growth factor receptor variant III (EGFRvIII) that constitutively secretes a signal regulatory protein gamma (SIRPgamma)-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eliminated EGFRvIII+ GBM in a dose-dependent manner in vitro and eradicated orthotopically xenografted EGFRvIII-mosaic GBM by locoregional application in vivo. This resulted in significant tumor-free long-term survival, followed by partial tumor control upon tumor re-challenge. Combining anti-CD47 antibodies with anti-EGFRvIII CAR T cells failed to achieve a similar therapeutic effect, underscoring the importance of sustained paracrine GAM modulation. Multidimensional brain immunofluorescence microscopy and in-depth spectral flow cytometry on GBM-xenografted brains showed that anti-EGFRvIII-SGRP CAR T cells accelerated GBM clearance, increased CD68+ cell trafficking to tumor scar sites and promoted GAM-mediated tumor cell uptake. In a peripheral lymphoma mouse xenograft model, anti-CD19-SGRP CAR T cells had superior efficacy to conventional anti-CD19 CAR T cells. Validation on human GBM explants revealed that anti-EGFRvIII-SGRP CAR T cells had a similar tumor-killing capacity to anti-EGFRvIII CAR monotherapy but showed a slight improvement in the maintenance of tumor-infiltrated CD14+ cells. Thus, local anti-EGFRvIII-SGRP CAR T cell therapy combines the potent antitumor effect of engineered T cells with the modulation of the surrounding innate immune TME. This results in the additive elimination of bystander EGFRvIII- tumor cells in a manner that overcomes the main mechanisms of CAR T cell therapy resistance, including tumor innate immune suppression and antigen escape.

Dataset Information

Regulatory programs of B-cell activation and germinal center reaction allow for B-ALL escape from CD19 CAR T-cell therapy

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets