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Natural and non-natural cytokine receptors generate diverse cell states to enhance T cell therapy

ABSTRACT: Cytokines augment T cell function, but the nature of the optimal signals are not well defined. We deployed orthogonal cytokine-receptors to diversify the JAK/STAT signaling profiles elicited by orthogonal IL-2. We designed chimeric receptors consisting of the orthogonal IL-2 receptor extracellular domain (ECD) fused to intracellular domains (ICDs) from receptors for other common gamma chain cytokines as well as ICDs from interferon receptor, IL-10 receptor and homodimeric receptor families not expressed on T cells. Such non-natural pairings with the common gamma chain expand the JAK/STAT signaling space in T cells. Natural and non-natural orthogonal chimeric receptors led to distinct T cell fates in tumors, including naturally occurring states (Tc2 differentiation driven by orthogonal chimeric IL4R) and synthetic states (myeloid-like T cells driven by orthogonal chimeric granulocyte colony stimulating factor receptor). The orthogonal chimeric IL22R (o22R) potently activated STAT-1, -3, -4, and -5, imparting T cells with stem-like and effector properties. The pronounced anti-tumor functionality mediated by o22R and oGCSFR was linked to remodeling of the exhaustion-associated epigenome. Our study broadens the cytokine receptor repertoire, providing novel solutions to overcome barriers for using engineered T cells to treat cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272385 | GEO | 2024/07/29

REPOSITORIES: GEO

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Project description:Dendritic cells (DCs) are key initiators of the adaptive immunity, and upon recognition of pathogens are able to skew T cell differentiation to elicit appropriate responses. DCs possess this extraordinary capacity to discern external signals using receptors that recognize pathogen-associated molecular patterns. These can be glycan-binding receptors that recognize carbohydrate structures on pathogens or pathogen-associated patterns that additionally bind receptors, such as Toll-like receptors (TLRs). This study explores the early signaling events in DCs upon binding of α2-3 sialic acid (α2-3sia) that are recognized by Immune inhibitory Sialic acid binding immunoglobulin type lectins. α2-3sias are commonly found on bacteria, e.g. Group B Streptococcus, but can also be expressed by tumor cells. We investigated whether α2-3sia conjugated to a dendrimeric core alters DC signaling properties. Through phosphoproteomic analysis, we found differential signaling profiles in DCs after α2-3sia binding alone or in combination with LPS/TLR4 co-stimulation. α2-3sia was able to modulate the TLR4 signaling cascade, resulting in 109 altered phosphoproteins. These phosphoproteins were annotated to seven biological processes, including the regulation of the IL-12 cytokine pathway. Secretion of IL-10, the inhibitory regulator of IL-12 production, by DCs was found upregulated after overnight stimulation with the α2-3sia dendrimer. Analysis of kinase activity revealed altered signatures in the JAK-STAT signaling pathway. PhosphoSTAT3 (Ser727) and phosphoSTAT5A (Ser780), involved in the regulation of the IL-12 pathway, were both downregulated. Flow cytometric quantification indeed revealed de- phosphorylation over time upon stimulation with α2-3sia, but no α2-6sia. Inhibition of both STAT3 and -5A in moDCs resulted in a similar cytokine secretion profile as α-3sia triggered DCs. Conclusively, this study revealed a specific alteration of the JAK-STAT pathway in DCs upon simultaneous α2-3sia and LPS stimulation, altering the IL10:IL-12 cytokine secretion profile associated with reduction of inflammation. Targeted control of the STAT phosphorylation status is therefore an interesting lead for the abrogation of immune escape that bacteria or tumors impose on the host.

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Natural and non-natural cytokine receptors generate diverse cell states to enhance T cell therapy

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