Purpose: To identify immune subtypes and investigate the immune landscape of squamous cell carcinomas (SCC), which share common etiology and histologic features.Experimental Design: 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.Results: 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 þ T cells, activated NK cells, and elevated IFNg response. Accordingly, these patients had the best prognosis. A third subtype was dominated by M2-polarized macrophages with potent immunesuppressive factors such as TGFb 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.Conclusions: 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. NOTE: Immune subtype 4 was used as the baseline for survival risk comparison for immune subtype variable. CESC was used as the baseline for survival risk comparison for cancer type variable. Stage I was used as the baseline for survival risk comparison for stage variable. Ã , P < 0.1; ÃÃ , P < 0.05; ÃÃÃ , P < 0.01. Li et al. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): B. LiAnalysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

Hypoxia is an independent prognostic indicator of poor outcome in several malignancies. However, precise mechanism through which hypoxia promotes disease aggressiveness is still unclear. Here, we report that under hypoxia (1% O2), human prostate cancer (PCA) cells, and extracellular vesicles (EVs) released by these cells, are significantly enriched in triglycerides due to the activation of lipogenesis-related enzymes and signaling molecules. This is likely a survival response to hypoxic stress as accumulated lipids could support growth following reoxygenation. Consistent with this, significantly higher proliferation was observed in hypoxic PCA cells following reoxygenation associated with rapid use of accumulated lipids. Importantly, lipid utilization inhibition by CPT1 inhibitor etomoxir and shRNA-mediated CPT1-knockdown significantly compromised hypoxic PCA cell proliferation following reoxygenation. Furthermore, COX2 inhibitor celecoxib strongly reduced growth and invasiveness following hypoxic PCA cells reoxygenation, and inhibited invasiveness induced by hypoxic PCA EVs. This establishes a role for COX2 enzymatic products in the enhanced PCA growth and invasiveness. Importantly, concentration and loading of EVs secreted by PCA cells were significantly compromised under delipidized serum condition and by lipogenesis inhibitors (fatostatin and silibinin). Overall, present study highlights the biological significance of lipid accumulation in hypoxic PCA cells and its therapeutic relevance in PCA.

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