Dissecting the Immunological Profiles in NSD3-Amplified LUSC through Integrative Multi-Scale Analyses

SIMPLE SUMMARY: Although cancer immunotherapy has become a “game changer” in treating LUSC patients, challenges still prevail due to the heterogeneous response and insufficient predictive biomarkers. Recently, NSD3, a neighbor gene of FGFR1, was identified as a key genetic driver of LUSC tumorigenesis. While previous studies have reported the relevance of NSD3 in innate antiviral immunity, the association of NSD3 with the TIME remains an open question requiring further investigation. We first show that NSD3 gene amplification is associated with an immune-desert phenotype and correlated with a worse immunotherapy outcome. Further molecular characterizations pinpoint that the high activity of UPR signaling might be a pivotal mediator for the non-inflamed TME phenotype of NSD3-amplified LUSC. Concordantly, the pharmaco-transcriptomic correlation analysis indicated that the intervention of UPR signaling could be a promising synthetic lethality target for NSD3-amplified LUSC. Our findings reveal a previously unappreciated immunological role for NSD3 in LUSC pathobiology and provide therapeutic rationales for this daunting disease. ABSTRACT: The histone H3 lysine 36 (H3K36) methyltransferase NSD3, a neighboring gene of FGFR1, has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the immunological roles of NSD3 in driving carcinogenesis, are poorly understood. In this study, we systematically integrated multi-omics data (e.g., genome, transcriptome, proteome, and TMA array) to dissect the immunological profiles in NSD3-amplified LUSC. Next, pharmaco-transcriptomic correlation analysis was implemented to identify the molecular underpinnings and therapeutic vulnerabilities in LUSC. We revealed that NSD3-amplified LUSC presents a non-inflamed tumor immune microenvironment (TIME) state in multiple independent LUSC patient cohorts. Predictably, elevated NSD3 expression was correlated with a worse immunotherapy outcome. Further molecular characterizations revealed that the high activity of unfolded protein response (UPR) signaling might be a pivotal mediator for the non-immunogenic phenotype of NSD3-amplified LUSC. Concordantly, we showed that NSD3-amplified LUSCs exhibited a more sensitive phenotype to compounds targeting UPR branches than the wild-type group. In brief, our multi-level analyses point to a previously unappreciated immunological role for NSD3 and provide therapeutic rationales for NSD3-amplified squamous lung cancer.