Interrogation of T Cell-Enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism

Background: The presence of cytotoxic tumor infiltrating lymphocytes (TILs) and antigen (e.g., viral, tumor neoantigens) enhances anti-tumor immunity. However, features including recruitment of tolerogenic cell types, nutrient-depletion, and the establishment of an acidic and hypoxic microenvironment diminish anti-tumor lymphocyte function. We sought to understand why the anti-tumor immune response fails despite a favorable immune profile. Methods: We leveraged human papillomavirus-related (HPV+) head and neck squamous cell carcinomas (HNSC) to address this question given their high degree of CD8+ T cell-infiltration and virus-derived tumor-associated antigens. We evaluated expression of 2,520 metabolic genes between HPV+ HNSCs of different prognostic phenotypes. We further tested tumor-intrinsic and -extrinsic sources of polyamine (PA) gene expression based on observations from the prior analysis. We used bulk RNAseq from The Cancer Genome Atlas (TCGA; 10 different cancers) and single cell (sc) RNAseq data from two atlases to parse immune cell contributions to polyamine gene expression. We used TCGA data and an immunotherapy-treated melanoma cohort to examine survival outcomes as a function of polyamine gene set expression. Results: PA metabolism genes were upregulated in aggressive phenotype, T cell-enriched (Thi), HPV+ HNSCs. PA synthesis and transporter gene enrichment was associated with T cell infiltration, recurrent or persistent cancer, overall survival status, primary site, molecular subtype, and MYC genomic alterations. PA synthesis and transport gene sets were more highly expressed in HPV- compared to HPV+ HNSCs. Bulk and scRNAseq data from HPV+ HNSCs demonstrated greater PA catabolism gene set expression among myeloid cells. A combined PA gene set comprised of genes involved in PA synthesis and transport was negatively correlated with cytotoxic T cell functional score across TCGA tumor types. Combined PA gene set expression was associated with greater mortality risk across five tumor types and worse survival in T cell-infiltrated, anti-PD-1-treated melanomas. Conclusions: A genomic approach leveraging T cell-infiltrated, immunogenic HPV+ HNSCs revealed an association between polyamine metabolism, anti-tumor immunity, and prognosis across several cancer types. These data address hurdles to anti-tumor immunity and immunotherapy and warrant further investigation of polyamines as a biomarker for targeted therapy in the context of a T cell-infiltrated microenvironment.