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IL-27 and TCR stimulation promote T cell expression of multiple inhibitory receptors

ABSTRACT: Inhibitory receptors (IR) are a diverse group of cell surface molecules that modulate T cell activation, but there are gaps in our knowledge of the cell extrinsic factors that regulate their expression. The present study found that in vivo overexpression of IL-27 led to increased T cell expression of PD-L1, LAG-3, TIGIT, and TIM-3. In vitro, TCR stimulation alone promoted expression of multiple IRs, while IL-27 alone induced expression of PD-L1. However, the combination of intermediate TCR stimulation and IL-27 resulted in synergistic induction of LAG-3, CTLA-4, and TIGIT. In vivo, infection with Toxoplasma gondii resulted in parasitespecific effector T cells that expressed high levels of IR and at local sites of infection where IL-27 production was highest, IL-27 was required for maximal effector cell expression of PD-L1, LAG-3, CTLA-4 and TIGIT. Together, these results affirm the critical role of TCR signals in the induction of IR expression, but find that during infection, IL-27 provides a signal that promotes T cell expression of inhibitory receptors.

ORGANISM(S): Mus musculus

PROVIDER: GSE124222 | GEO | 2019/01/17

REPOSITORIES: GEO

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Project description:CD19-targeting chimeric antigen receptor (CAR) T cell have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, according to the recent clinical data, a significant portion of patients still do not benefit from the therapy, due various resistance mechanisms including the high expression of multiple inhibitory immune checkpoint receptors on activated CAR-T cells. Studies of checkpoint blockade immunotherapy using monoclonal antibodies have shown that simultaneously targeting inhibitory receptors that are functionally non-redundant can synergistically enhance anti-tumor responses. Here we report a lentiviral two-in-one CAR T approach in which two checkpoint receptors can be downregulated simultaneously by a dual short-hairpin RNA (shRNA) cassette integrated into a CAR vector. Using this system, we evaluated CD19-targeting CAR T cells in the context of four different checkpoint combinations, PD-1/TIM-3, PD-1/LAG-3, PD-1/CTLA-4, and PD-1/TIGIT, and found that the CAR T with PD-1/TIGIT downregulation uniquely exhibited synergistic anti-tumor effect in mouse xenograft models compared to the single PD-1 downregulation and maintained cytolytic and proliferative capacity upon repeated antigen exposure. Importantly, functional and phenotypic analysis of CAR T cells as well as analysis of transcriptomic profiles suggests that downregulation of PD-1 enhances short-term effector function while downregulation of TIGIT is primarily responsible for maintaining a less-differentiated/exhausted state, providing a potential mechanism of the synergy. The PD-1/TIGIT downregulated CAR T cells generated from DLBCL patient-derived T cells following clinically applicable manufacturing process also showed a robust anti-tumor activity and significantly improved persistence in vivo compared to conventional CD19-targeting CAR T cells. Overall, our results demonstrate that the cell-intrinsic PD-1/TIGIT dual downregulation strategy may provide an effective way to overcome the immune checkpoint-mediated resistance in CAR T therapy.

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IL-27 and TCR stimulation promote T cell expression of multiple inhibitory receptors

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