Jin Ng, Yue You, Tina Z Zhang, Jonas B Hess, Sarah A Best, Alex Caneborg, Marcel Schmiel, Sarah T Diepstraten, Tim Spelman, Joshua I Gray, Dale I Godfrey, Yin Wu, Richard W Tothill, Casey J A Anttila, Tracey M Baldwin, Shalin H Naik, Daniela Amann-Zalcenstein, Ariena J Kersbergen, Tracy L Leong, Julie George, Matthew E Ritchie, Nicholas A Gherardin, Hui-Fern Koay, Peter F Hickey, Daniel Steinfort, Kate D Sutherland
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.