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.
Jin Ng, Yue You, Tina Zhang et al.· Cancer Cell· 0 citations
Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMBhigh tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC – as a TMBhigh cancer – relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.
Lucia A. Torres-Fernández, V. Boehm, Joel Kaufmann et al.· Molecular Cancer· 0 citations
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