HISMD: A Novel Immune Subtyping System for HNSCC.

Immune subtyping is an important way to reveal immune heterogeneity, which may contribute to the diversity of the progression and treatment in head and neck squamous cell carcinoma (HNSCC). However, reported immune subtypes mainly focus on levels of immune infiltration and are mostly based on a mono-omics profile. This study aimed to identify a comprehensive immune subtype for HNSCC via multi-omics clustering and build a novel subtype prediction system for clinical application. Data were obtained from The Cancer Genome Atlas database and our independent multicenter cohort. Multi-omics clustering was performed to identify 3 clusters of 499 patients in The Cancer Genome Atlas based on immune-related gene expression and somatic mutations. The immune characteristics and biological features of the obtained clusters were revealed by bioinformatics, and 3 immune subtypes were identified: 1) adaptive immune activation subtype predominantly enriched in T cells, 2) innate immune activation subtype predominantly enriched in macrophages, and 3) immune desert subtype. Subsequently, the clinical implications of each subtype were analyzed per clinical epidemiology. We found that adaptive immune activation showed better survival outcomes and had a similar response to chemotherapy with innate immune activation, whereas immune desert might be relatively resistant to chemotherapy. Moreover, a subtype prediction system was developed by deep learning with whole slide images and named HISMD: HNSCC Immune Subtypes via Multi-omics and Deep Learning. We endowed HISMD with interpretability through image-based key feature extraction. The clinical implications, biological significances, and predictive stability of HISMD were successfully verified by using our independent multicenter cohort data set. In summary, this study revealed the immune heterogeneity of HNSCC and obtained a novel, highly accurate, and interpretable immune subtyping prediction system. For clinical implementation in the future, additional validation and utility studies are warranted.