8084 Background: Antigen-presenting machinery (APM) is critical for tumor immune recognition. The loss of APM promotes immune evasion and immunotherapy resistance in cancers, including small-cell lung cancer (SCLC). SCLC has a high tumor mutational burden (TMB), and it displays profound APM suppression, explaining its weak response to immune checkpoint inhibitors. We aimed to capture APM gene expression in a large real-world cohort (RWC) and prospective clinical trial datasets to address the clinical implications of APM suppression for current treatment strategies. Methods: We calculated a classical antigen-presenting MHCs (CAMs) score using a gene signature comprised of 18 genes closely associated with MHC-I expression and antigen presentation. We evaluated this score in 6,000 real-world lung cancer samples and in the transcriptomic dataset of a Phase III clinical trial evaluating the effect of chemo-immunotherapy as a first-line treatment in extensive-stage SCLC (IMpower133). Transcriptomic, genomic, and proteomic data were collected for analysis. Results: Patients with SCLC were stratified into 3 groups according to hierarchical clustering of CAM gene expression for functional enrichment, differential gene expression, response to drug, and survival analyses. CAM expression was markedly suppressed in SCLC compared to other lung cancer histologies. In SCLC, CAM-low accounted for 53% of patients, followed by CAM-intermediate (40%) and -high (7%). We found no statistical difference in TMB-high (³10 mutations/Mb) proportion across CAM groups. CAM-intermediate- and high groups had lower TP53, RB1, and PTEN mutation rates and a higher PI3K mutation rate compared to CAM-low. CAM-low tumors displayed the highest DNA damage response and neuroendocrine signature scores and the lowest RB1 expression. CAM-low tumors showed the lowest expression of cytokine and cytokine receptors involved in lymphocyte trafficking, as well as the lowest CD8⁺/Treg and M1/M2 ratios, consistent with a highly immunosuppressive context. CAM-low and intermediate groups had the lower PD-L1 expression and worse overall survival from the start of chemoimmunotherapy in the RWC. Most targetable markers, such as DLL3, were down-regulated in CAM-low tumors. We also identified high expression of novel immune targets in the CAM-low population that may inform future drug design. Conclusions: We demonstrate that in RWC and clinical trial samples, most patients with SCLC are CAM-low, exhibit immune evasion features, and have poor outcomes, as well as reduced expression of most druggable targets. Our data suggests that SCLC’s immunosuppressive microenvironment may lessen the efficacy of new-generation compounds. We highlight potential novel treatment strategies targeting defective APM tumors that may activate the immune microenvironment and augment the effect of existing immunotherapy agents.
Sen et al. (Thu,) studied this question.