The Immune Subtypes and Landscape of Squamous Cell Carcinoma

To identify immune subtypes and investigate the immune landscape of squamous cell carcinomas (SCC), which share common etiology and histologic features.

Based on the immune gene expression profiles of 1,368 patients with SCC in the Cancer Genome Atlas (TCGA), we used consensus clustering to identify robust clusters of patients and assessed their reproducibility in an independent pan-SCC cohort of 938 patients. We further applied graph structure learning-based dimensionality reduction to the immune profiles to visualize the distribution of individual patients.

We identified and independently validated six reproducible immune subtypes associated with distinct molecular characteristics and clinical outcomes. An immune-cold subtype had the least amount of lymphocyte infiltration and a high level of aneuploidy, and these patients had the worst prognosis. By contrast, an immune-hot subtype demonstrated the highest infiltration of CD8⁺ T cells, activated NK cells, and elevated IFNγ response. Accordingly, these patients had the best prognosis. A third subtype was dominated by M2-polarized macrophages with potent immune-suppressive factors such as TGFβ signaling and reactive stroma, and these patients had relatively inferior prognosis. Other subtypes showed more diverse immunologic features with intermediate prognoses. Finally, our analysis revealed a complex immune landscape consisting of both discrete clusters and continuous spectrum.

This study provides a conceptual framework to understand the tumor immune microenvironment of SCCs. Future work is needed to evaluate its relevance in the design of combination treatment strategies and guiding optimal selection of patients for immunotherapy.