Biology subjects

Schmiel, M.

Publications and source records attributed to Schmiel, M..

3 recordsLinked to original sources

bioRxiv2026

A targetable dependency on nonsense-mediated decay for proteostasis and immune control in small cell lung cancer

Small cell lung cancer (SCLC) is among the deadliest cancers with excessive somatic alterations, expectedly resulting in immunogenic epitopes. However, patient benefit from immunotherapy is limited. 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 depends on NMD for cellular homeostasis and immune evasion. NMD inhibition impaired SCLC proliferation and induced ER stress-dependent apoptosis in a TMB-dependent manner, thereby enabling pharmacological inhibition in vivo which effectively controlled tumor growth. 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.

cancer biology↗

bioRxiv2025

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

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.

cancer biology↗

bioRxiv2022

NEMO- and RelA-dependent NF-kB Signaling Promotes Small Cell Lung Cancer

Small cell lung cancer (SCLC) is an aggressive type of lung cancer driven by combined loss of the tumor suppressors RB1 and TP53. SCLC is highly metastatic and despite good initial response to chemotherapy patients usually relapse, resulting in poor survival. Therefore, better understanding of the mechanisms driving SCLC pathogenesis is required to identify new therapeutic targets. Here we identified a critical role of the IKK/NF-{kappa}B signaling pathway in SCLC development. Using a relevant mouse model of SCLC, we found that ablation of NEMO/IKK{gamma}, the regulatory subunit of the IKK complex that is essential for activation of canonical NF-{kappa}B signaling, strongly delayed the onset and growth of SCLC resulting in considerably prolonged survival. In addition, ablation of the main NF-{kappa}B family member p65/RelA also delayed the onset and growth of SCLC and prolonged survival, albeit to a lesser extent than NEMO. Interestingly, constitutive activation of IKK/NF-{kappa}B signaling within the tumor cells did not exacerbate the pathogenesis of SCLC, suggesting that endogenous NF-{kappa}B levels are sufficient to fully support tumor development. Moreover, TNFR1 deficiency did not affect the development of SCLC, showing that TNF signaling does not play an important role in this tumor type. Taken together, our results revealed that IKK/NF-{kappa}B signaling plays an important role in promoting SCLC, identifying the IKK/NF-{kappa}B pathway as a promising therapeutic target.

cancer biology↗