Spatially preserved multi-region transcriptomic subtyping and biomarkers of outcome with chemoimmunotherapy in extensive-stage small cell lung cancer [IMfirst_DSP cohort]

Transcriptomic subtyping holds promise for personalized therapy in extensive stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers associated with long-term chemoimmunotherapy benefit in human ES-SCLC. Our work highlights that high intratumoral heterogeneity, lack of consistent association with outcome, and unclear subtype-specific target expression are major challenges for SCLC subtype-based precision oncology. Pre-existing IFNϒ-driven immunity and mitochondrial metabolism seem key correlates of long-term efficacy for chemoimmunotherapy in ES-SCLC. We used tumor samples from 32 ES-SCLC patients enrolled in the IMfirst clinical trial (EudraCT Number: 2019-002784-10) with adequate tumor material for spatially preserved transcriptomic analysis. The IMfirst study was a phase IIIb single arm multicenter trial evaluating the safety and effectiveness of PD-L1 blockade (atezolizumab) in combination with platinum-etoposide as first-line treatment in patients with ES-SCLC. We retrieved pre-treatment, formalin-fixed and paraffin-embedded (FFPE), tumor specimens, which were centrally reviewed by an expert pathologist at the 12 de Octubre research facilities (Madrid, Spain). Spatial mRNA profiling was done using the GeoMx Digital Spatial Profiling (DSP) system (NanoString). For this study, we used an mRNA assay that contained oligo-nucleotide-labeled, photocleavable, RNA-binding probes targeting the expression of ~1800 genes related to cancer pathways and anti-tumor immunity (Cancer Transcriptome Atlas, CTA, NanoString) plus additional custom-designed probes targeting the expression of three SCLC subtype-defining transcription factors not included in the CTA panel (NEUROD1, POU2F3, and YAP1).