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

SUMMARY 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 γδ T cell infiltration in biospecimens from patients with SCLC. Despite PD-1 expression, γδ T cells maintained a cytotoxic transcriptional profile, suggestive of an anti-tumor role. Indeed, high γδ T cell infiltration predicted improved response to anti-PD-L1 immunotherapy in patients with SCLC. Moreover, using pre-clinical models, we demonstrated that γδ T cells are effective at tarlatamab (DLL3-CD3 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. Competing Interest Statement D.I.G. and N.A.G. are inventors on two patents regarding activation of γδ T cells. J.G. is consultant to DISCO Pharmaceuticals and received honoraria from MSD and Boehringer Ingelheim. K.D.S received honoraria from Boehringer Ingelheim unrelated to this work.