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

Ng, J.; You, Y.; Zhang, T. Z.; Hess, J. B.; Best, S. A.; Caneborg, A.; Schmiel, M.; Godfrey, D. I.; Wu, Y.; Tothill, R. W.; Antilla, C. J. A.; Baldwin, T. M.; Naik, S. H.; Amman-Zalcenstein, D.; Kersbergen, A. J.; Leong, T. L.; George, J.; Ritchie, M. E.; Gherardin, N. A.; Koay, H.-F.; Hickey, P. F.; Steinfort, D.; Sutherland, K. D.

doi:10.1101/2025.09.04.674147

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bioRxiv · 10.1101/2025.09.04.674147

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

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Abstract

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.

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Ng, J., You, Y., Zhang, T. Z., Hess, J. B., Best, S. A., Caneborg, A., Schmiel, M., Godfrey, D. I., Wu, Y., Tothill, R. W., Antilla, C. J. A., Baldwin, T. M., Naik, S. H., Amman-Zalcenstein, D., Kersbergen, A. J., Leong, T. L., George, J., Ritchie, M. E., Gherardin, N. A., Koay, H.-F., Hickey, P. F., Steinfort, D., Sutherland, K. D.. 2025-09-04. γδ T cells modulate anti-tumor immunity in small cell lung cancer. https://doi.org/10.1101/2025.09.04.674147

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