Determining Previously Undefined Immune Regulatory Networks in Regulatory T Cells and Innate Lymphoid Cells within the Tumour Microenvironment

Abstract

Regulatory T cells (Tregs) are essential for immune suppression, employing multiple mechanisms, including co-inhibitory receptor expression. However, the role of the programmed cell death-1 receptor (PD-1) in Treg function remains controversial. Here, we identify PD-1 as a key checkpoint in Tregs, orchestrating a unique co-inhibitory receptor network that shapes their function in tumour immunity. We demonstrate that PD-1 regulates the expression and activity of CD30, a central driver of Treg suppressive function within the tumour microenvironment (TME). Mechanistically, PD-1 deficiency amplifies STAT5 signalling in Tregs, leading to upregulated CD30 expression and thus suppressive capacity. Consistently, in stage IV metastatic melanoma patients, anti-PD-1-resistant individuals exhibit increased CD30 expression on Tregs compared to responders. Thus, we uncover a novel role for PD-1 in restraining CD30 expression, thereby modulating Treg-mediated immunosuppression. These insights provide a rationale for targeting PD-1 and CD30 in combination therapies to improve cancer treatment outcomes. Innate lymphoid cells (ILCs) also play a crucial role in tissue immunity and are influenced by co-receptor signalling. Here, we define a subset of tumour-infiltrating ILCs characterised as Tbet⁺NK1.1⁻, which express PD-1 within the TME. We demonstrate that PD-1 profoundly regulates the function of Tbet⁺NK1.1⁻ ILCs in murine B16 melanoma. PD-1-deficient Tbet⁺NK1.1⁻ ILCs exhibit significantly increased production of IFN-γ, granzyme B, and granzyme K, correlating with diminished tumour growth. These findings highlight a novel regulatory axis through which PD 1 modulates anti-tumour responses in ILCs, suggesting potential therapeutic avenues to enhance immune-mediated tumour clearance.