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Cell-based models of ‘Cytokine Release Syndrome’ endorse CD40L and GM-CSF knockout in CAR T cells as mitigation strategy

ABSTRACT: Cell-based models of ‘Cytokine Release Syndrome’ endorse CD40L and GM-CSF knockout in CAR T cells as mitigation strategy

PROVIDER: PRJNA1018974 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26113746_1.fastq.gz	Fastqsanger.gz
	SRR26113746_2.fastq.gz	Fastqsanger.gz
	SRR26113747_1.fastq.gz	Fastqsanger.gz
	SRR26113747_2.fastq.gz	Fastqsanger.gz
	SRR26113748_1.fastq.gz	Fastqsanger.gz

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Cell-based models of ‘Cytokine Release Syndrome’ endorse CD40L and GM-CSF knockout in CAR T cells as mitigation strategy

Project description:Chimeric antigen receptor (CAR) T cells are engineered lymphocytes able to recognize and eradicate cancer cells. While CAR T cell therapy has shown promising outcomes in patients with hematologic malignancies, it can cause undesirable side-effects such as cytokine release syndrome (CRS). CRS is triggered by CAR T cell-based activation of monocytes, which are stimulated via the CD40L–CD40R axis or via uptake of GM-CSF to secrete pro-inflammatory cytokines. Mouse models have been used to model CRS but they are labor intensive and not amenable to screening approaches. To overcome this challenge, we established two cell-based CRS in vitro models that entail the co-culturing of leukemic B cells with CD19-targeting CAR T cells and primary monocytes from the same donor. Upon antigen encounter, CAR T cells upregulated CD40L and GM-CSF which stimulated the monocytes to release IL-6. To endorse these models, we demonstrated that neutralizing antibodies or genetic disruption of the CD40L and/or CSF2 loci in CAR T cells using CRISPR-Cas technology significantly reduced IL-6 secretion by bystander monocytes without affecting the cytolytic activity of the engineered lymphocytes. Overall, our cell-based models were able to recapitulate CRS in vitro, allowing us to validate mitigation strategies based on antibodies or genome editing.

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Project description:GM-CSF is involved in immune complex (IC)-mediated arthritis. However, little is known about what is the cellular source of GM-CSF and how it is regulated during IC-mediated inflammation. Using novel GM-CSF reporter mice, we show that NK cells produce GM-CSF during an IC-mediated model of inflammatory arthritis. NK cells promoted STIA in a GM-CSF-dependent manner, as deletion of NK cells and selective removal of GM-CSF production by NK cells abrogated disease. Furthermore, we show that myeloid cell activation by GM-CSF is restrained by induction of JAK/STAT checkpoint inhibitor cytokine-inducible SH2-containing protein, CIS. Myeloid cells from CIS-deficient mice had exaggerated responses to GM-CSF, and these mice develop exacerbated STIA. Our data suggest that tissue NK cells may amplify joint inflammation in arthritis via GM-CSF production and thus represent a novel target in IC-mediated pathology. Endogenous CIS provides a key brake on signaling through the GM-CSF receptor and strategies that boost its function may provide an alternative anti-inflammatory approach.

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Project description:Human and murine studies showed that granulocyte macrophage colony-stimulating factor (GM-CSF) exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF-activated monocytes (GMaM). We used microarray technology and functional assays to characterize GMaM in vitro and used a mouse model of colitis to study GMaM functions in vivo. Peripheral blood monocytes where cultured 16 h with media containing AB serum (control monocytes) or media containing 10 ng/mL GM-CSF and AB serum (GM-CSF activated monocytes). In three independent experiments, total RNA from GMaM and control monocytes was isolated and processed for microarray hybridization.

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