Biology subjects

Koay, H.-F.

Publications and source records attributed to Koay, H.-F..

3 recordsLinked to original sources

bioRxiv2025

γδ T cells modulate anti-tumor immunity in small cell lung cancer

Small cell lung cancer (SCLC) is a highly aggressive neoplasm with limited sensitivity to anti-PD-(L)1 blockade, likely due to the epigenetic silencing of MHC-I. Elucidating MHC-I-independent immune recognition mechanisms is therefore crucial for enhancing treatment responses and improving clinical outcomes in a greater number of patients. Leveraging single cell approaches, we discovered {gamma}{delta} T cell infiltration in biospecimens from patients with SCLC. Despite PD-1 expression, {gamma}{delta} T cells maintained a cytotoxic transcriptional profile, suggestive of an anti-tumor role. Indeed, high {gamma}{delta} T cell infiltration predicted improved response to anti-PD-L1 immunotherapy in patients with SCLC. Moreover, using pre-clinical models, we demonstrated that {gamma}{delta} T cells are effective at tarlatamab (DLL3-CD3 BiTE) redirected SCLC killing and that zoledronate, an FDA-approved compound, can sensitize SCLC cells to {gamma}{delta} T cell-mediated killing. Thus, our findings suggest that engaged {gamma}{delta} T cells are potentially valuable targets for SCLC therapy.

cancer biology↗

bioRxiv2024

Vgamma1+ gammadelta T cell-derived IL-4 initiates CD8 T cell immunity

Dendritic cells (DC) are pivotal for initiating adaptive immunity, a process triggered by the activation of DC via pathogen products or damage. Here, we describe an additional layer to this process, essential when pathogen-derived signals alone cannot directly achieve full DC activation. Immunisation with sporozoites from Plasmodium leads to CD8 T cell priming in a complex response that is initiated by a collaboration between conventional type 1 DC (cDC1) and {gamma}{delta} T cells. We unveil a pivotal initiating role for V{gamma}1+ {gamma}{delta} T cells, as they directly supply IL-4 to DC and CD8 T cells. IL-4 synergises with a CD4 T cell-derived CD40L signal to induce IL-12 production by cDC1. Both IL-12 and IL-4 then directly signal CD8 T cells, with synergy between these cytokines driving enhanced IL-12 receptor expression and expansion of responding CD8 T cells. This study reveals a key role for V{gamma}l+ {gamma}{delta} T cells in initiating CD8 T cell immunity to Plasmodium. More broadly, it shows that responses to some pathogens require help from innate-like T cells to pass an initiation threshold and further amplify the response in a process underscored by IL-4 production.

immunology↗

bioRxiv2024

Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signalling

Unconventional T cells, including mucosal-associated invariant T (MAIT), natural killer T (NKT), and gamma-delta T ({gamma}{delta}T) cells, comprise distinct T-bet+, IFN-{gamma}+ and ROR{gamma}t+, IL-17+ subsets which play differential roles in health and disease. NKT1 cells are susceptible to ARTC2-mediated P2X7 receptor (P2RX7) activation, but the effects on other unconventional T-cell types are unknown. Here, we show that MAIT, {gamma}{delta}T, and NKT cells express P2RX7 and are sensitive to P2RX7-mediated cell death. Mouse peripheral T-bet+ MAIT1, {gamma}{delta}T1, and NKT1 cells, especially in liver, co-express ARTC2 and P2RX7, which can be further upregulated by retinoic acid. Blocking ARTC2 or inhibiting P2RX7 protected MAIT1, {gamma}{delta}T1, and NKT1 cells from cell death, enhanced their survival in vivo, and increased the number of IFN-{gamma}-secreting cells without affecting IL-17 production. Importantly, this revealed the existence of IFN-{gamma} and IL-4 co-producing unconventional T-cell populations normally lost upon isolation due to ARTC2/P2RX7-induced death. Administering extracellular NAD in vivo activated this pathway, depleting P2RX7-sensitive unconventional T cells. Our study reveals ARTC2/P2RX7 as a common regulatory axis modulating the unconventional T-cell compartment, affecting the viability of IFN-{gamma}- and IL-4-producing T cells, offering important insights to facilitate future studies into how these cells can be regulated in health and disease.

immunology↗