Abstract 7540: Impact of IL-2 and IL-7 on human regulatory T cell suppression and pembrolizumab-mediated reversal of human T cell exhaustion
Authors: Tut Gokhan , Harrison Neale , Sallie Leila , Welsh Emma , Pegg Ashley , Kaur Arshpreet , Li Zhi , Morano Ines , Chan Hujo , Cowley Jamie , Brady Catherine , Gordon John , Bryant Mark , Qureshi Omar , Barnes Nicholas M. 
Published: March 2024

Inhibitory pathways within the tumour microenvironment limit the anti-cancer immune response. Two central mechanisms limiting the T cell response in the tumour are suppression of effector T cells responses by regulatory T cells, and chronic exposure to tumour antigens that may bestow T cell unresponsiveness or exhaustion. Restoring exhausted T cell responsiveness through blockade of inhibitory immune checkpoints such as the PD-1/PDL-1 interaction is an established therapeutic modality leading to durable responses and improved survival rates in some patients.We have modelled suppressive mechanisms in vitro using purified human T cells and investigated the impact of the cytokines IL-2 and IL-7. A comparison of in vitro assay systems for T cell exhaustion including T cell/allogeneic dendritic cells, a recall response to a viral antigen, prolonged stimulation of T cells to generate an ‘exhausted’ phenotype followed by a secondary stimulation with allogeneic DCs, revealed in some donors, the greatest impact of pembrolizumab was with exhausted T cells, a finding consistent with our studies using a dissociated tumour cell response with primary cells from patients with lung or colon carcinomas. Quantifying a range of cytokines (e.g. IFNγ, TNFα and IL-10) and flow cytometry activation markers (e,g, CD69, CD25, CD71, OX40 and CD137) established that in general pembrolizumab was effective at restoring the IFNγ response, although some donors were not responsive, and there was a more modest impact on other readouts indicating not all T cell functionality is restored. We therefore tested the impact of IL-2 and IL-7 on the reversal of the ‘exhausted’ phenotype and identified further improved functionality and donor responsiveness. We subsequently tested the impact of these cytokines in another ‘inhibitory’ context, that of regulatory T cell suppression; we identified that high-levels of IL-2 overcame regulatory T cell suppression and IL-7 led to an overall enhancement of response.These findings highlight how multiple suppressive mechanisms may need to be overcome to maximally restore anti-cancer immune responses, and that the combination of cytokines, such as IL-2 and IL-7, and checkpoint inhibitors, such as pembrolizumab, may enhance T cell responses.

Citation Format: Gokhan Tut, Neale Harrison, Leila Sallie, Emma Welsh, Ashley Pegg, Arshpreet Kaur, Zhi Li, Ines Morano, Hujo Chan, Jamie Cowley, Catherine Brady, John Gordon, Mark Bryant, Omar Qureshi, Nicholas M. Barnes. Impact of IL-2 and IL-7 on human regulatory T cell suppression and pembrolizumab-mediated reversal of human T cell exhaustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7540.