IL-1 receptor-associated kinase 3 (IRAK3) in lung adenocarcinoma predicts prognosis and immunotherapy resistance: involvement of multiple inflammation-related pathways.

Background: Lung cancer is a globally prevailing malignancy, and the predominant histological subtype is lung adenocarcinoma (LUAD). IL-1 receptor-associated kinase 3 (IRAK3) has been identified in connection with innate immune and inflammatory response. The aim of this study is to investigate the impact of IRAK3 on prognosis and immunotherapy efficacy in LUAD, which remains incompletely elucidated.

Methods: Our study delved into multiple online databases to find out expression, methylation and prognostic potentials of IRAK3 in LUAD and other malignancies. We employed tissue microarrays to assess IRAK3 protein levels in our LUAD cohort [National Cancer Center (NCC), China] and explore prognostic values. The correlations between IRAK3 and immune infiltration based on The Cancer Genome Atlas (TCGA) data were analyzed by corresponding algorithms. The contribution of IRAK3 to immunotherapy response was explored through the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Both LinkedOmics database and gene set enrichment analysis (GSEA) were applied to investigate how IRAK3 influences the tumor immune microenvironment and regulates immunotherapy response. We applied single-cell RNA sequencing datasets for the investigation of IRAK3 expression across diverse immune cells. Moreover, we employed genomics of drug sensitivity in cancer (GDSC) databases to examine how IRKA3 expression correlates with different drug responses.

Results: Compared with normal tissues, various tumor tissues had lower IRAK3 expression which could be regulated by its high methylation level. Reduced IRAK3 protein level was observed to correlate with advanced tumor stages and unfavorable prognosis among patients with LUAD, especially individuals with lymph node metastasis. Gene set enrichment analysis (GSEA) and tumor infiltration analysis proved that IRAK3 provoked immune infiltration. Macrophages/monocytes, CD4⁺ T cells, CD8⁺ T cells and neutrophils correlated significantly with IRAK3 expression. With TIDE algorithm, IRAK3 was verified to be related to poor immune checkpoint blockade (ICB) response. IRAK3 demonstrated positive associations with T-cell dysfunction score and immune checkpoint markers. Conversely, it exhibited negative correlations with microsatellite instability (MSI) and tumor mutation burden (TMB). High IRAK3 expression exacerbated cytotoxic T lymphocyte (CTL) dysfunction and predicted immunotherapy resistance by involvement of multiple inflammation-related pathways including IL-6/JAK/STAT3 signaling, inflammatory response and interferon-gamma (IFN-γ) response pathways. Additionally, elevated IRAK3 expression was predicted to be related with better responses to chemotherapeutic and molecular targeted drugs.

Conclusions: Our findings indicated that IRAK3 could function as an independent prognostic predictor and an immunotherapeutic indicator in LUAD through involvement of multiple inflammation-related pathways.