γδ T cells modulate anti-tumor immunity in small cell lung cancer
- Author(s)
- Ng, J; You, Y; Zhang, TZ; Hess, JB; Best, SA; Caneborg, A; Schmiel, M; Diepstraten, ST; Spelman, T; Gray, JI; Godfrey, DI; Wu, Y; Tothill, RW; Anttila, CJA; Baldwin, TM; Naik, SH; Amann-Zalcenstein, D; Kersbergen, AJ; Leong, TL; George, J; Ritchie, ME; Gherardin, NA; Koay, HF; Hickey, PF; Steinfort, D; Sutherland, KD;
- Journal Title
- Cancer Cell
- Publication Type
- Online publication before print
- Abstract
- Small cell lung cancer (SCLC) is a highly aggressive neoplasm with limited sensitivity to anti-PD-(L)1 blockade, which is likely caused by 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 γδ T cell infiltration in biospecimens from patients with SCLC. Despite PD-1 expression, γδ T cells maintained a cytotoxic transcriptional profile, suggesting an anti-tumor role. Indeed, high γδ T cell infiltration in two practice-changing clinical trials predicted improved response to anti-PD-L1 immunotherapy in patients with SCLC. Moreover, using preclinical models, we demonstrated that γδ T cells are effective at tarlatamab (delta-like ligand 3 [DLL3]-CD3 bispecific T cell engager [BiTE])-redirected SCLC killing and that zoledronate, an FDA-approved compound, can sensitize SCLC cells to γδ T cell-mediated killing. Thus, our findings suggest that engaged γδ T cells are potentially valuable targets for SCLC therapy.
- Keywords
- immunotherapy; single-cell RNA sequencing; small cell lung cancer; tarlatamab; zoledronate; γδ T cells
- Department(s)
- Health Services Research; Collaborative Centre for Genomic Cancer Medicine
- Publisher's Version
- https://doi.org/10.1016/j.ccell.2026.08.015
- Open Access at Publisher's Site
https://doi.org/10.1016/j.ccell.2026.08.015- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-10-12 05:40:49
Last Modified: 2026-10-12 05:41:16