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

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.

NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions

“…Later, two studies reported the discovery and characterization of NSD3 PROTAC, being more efficient in blocking NSD3 function and decreasing Myc oncogenic node. Both PROTAC were synthesized incorporating an NSD3-PWWP antagonist link to an E3 ligase, showing the degradation of both NSD3 isoforms in cell lines of AML, multiple myeloma and lung cancer [64,85]. These studies correlate with our findings that NSD3S/MYC interaction stabilizes and activates MYC transcriptional activity.…”

“…It is accepted that innate and adaptive immunity plays important roles in tumor immune surveillance. Amplification of NSD3 in patients with LUSC exhibits a decrease in type II IFN response, leading to an immune-desert pro-tumorigenic phenotype [64]. In breast cancer, increased expression of NSD3 correlated with a decrease CD8+ T cells and increased PD-L1 gene [65], in agreement with Xu et al in lung cancer.…”

BAP1 Deficiency Inflames the Tumor Immune Microenvironment and Is a Candidate Biomarker for Immunotherapy Response in Malignant Pleural Mesothelioma

“…Transcriptomic data from immunotherapy-treated human renal cell carcinoma have been previously reported. 21 Data set from metastatic melanoma treated with checkpoint blockade immunotherapy were downloaded from https://ddbj.nig.ac.jp/resource/bioproject/PRJEB23709 .…”

“…The information on the 122 immunomodulators (MHC, immune receptors, chemokines, and immune stimulators) and 33 well-known effector genes of tumor-infiltrating immune cells was according to previous studies. 21 , 22 , 23 Gene signatures of 29 immune cell types and immune-related pathways were based on the previous study. 24 Exhausted and cytotoxic T-cell signatures were scored as the sum of the corresponding gene sets (exhausted: TIGIT, HAVCR2, CTLA4, LAG3, and PDCD1; cytotoxic: GZMA, GZMB, GZMK, IFNG, and IL2).…”

Immunotherapy for Solid Tumors

“…By utilizing multi-scale analyses (genome, transcriptome, proteome, and TMA array), ref. [ 2 ] provides the first evidence that NSD3 gene amplification defines a non-immunogenic phenotype in LUSC and is associated with poor immunotherapy outcomes. Additionally, the authors demonstrate that high unfolded protein response (UPR) promotes the “cold” tumor immune microenvironment of NSD3-amplified LUSC.…”