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Releasing the restraints of Vγ9Vδ2 T-cells in cancer immunotherapy

ABSTRACT: Objectives: Vγ9Vδ2 T-cells are a subset of T-cells with a crucial role in immunosurveillance which can be activated and expanded by multiple means to stimulate effector responses. Little is known about the expression of checkpoint molecules on this cell population and whether the ligation of these molecules can regulate their activity. The aim of this study was to assess the expression of both activatory and inhibitory receptors on Vγ9Vδ2 T-cells to assess potential avenues of regulation to target with immunotherapy. Methods: Expression of various activatory and inhibitory receptors was assessed on Vγ9Vδ2 T-cells by flow cytometry following activation and expansion using zoledronic acid (ZA) and Bacillus Calmette-Guérin (BCG). Expression of these markers and production of effector molecules was also examined following co-culture with various tumour cell targets. The effect of immune checkpoint blockade on Vγ9Vδ2 T-cells was also explored. Results: Vγ9Vδ2 T-cells expressed high levels of activatory markers both at baseline and following stimulation. Vγ9Vδ2 T-cells expressed variable levels of inhibitory checkpoint receptors with many being upregulated following stimulation. Expression of these markers is further modulated upon co- culture with tumour cells with changes reflecting activation and effector functions. Despite their high expression of inhibitory receptors when cultured with tumour cells expressing cognate ligands there was no effect on Vδ2+ T-cell cytotoxic capacity or cytokine production with immune checkpoint blockade. Conclusions: Our work suggests the expression of checkpoint receptors present on Vγ9Vδ2 T-cells which may provide a mechanism with the potential to be utilised by tumour cells to subvert Vγ9Vδ2 T-cell cytotoxicity. This work suggests important candidates for blockade by ICI therapy in order to increase the successful use of Vγ9Vδ2 T-cells in immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221563 | GEO | 2023/01/02

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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Releasing the restraints of Vγ9Vδ2 T-cells in cancer immunotherapy

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