Interrogation of T Cell–enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism

Metabolic features of the tumor microenvironment (TME) antagonize antitumor immunity. We hypothesized that T cell–infiltrated (Thi) tumors with a known antigen should exhibit superior clinical outcomes, though some fare worse given unfavorable metabolic features leveraging T cell–infiltrated (Thi), human papillomavirus–related (HPV⁺) head and neck squamous cell carcinomas (HNSC) to test this hypothesis. Expression of 2,520 metabolic genes was analyzed among Thi HPV⁺ HNSCs stratified by high-risk molecular subtype. RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA; 10 cancer types), single-cell RNA-seq data, and an immunotherapy-treated melanoma cohort were used to test the association between metabolic gene expression and clinical outcomes and contribution of tumor versus stromal cells to metabolic gene expression. Polyamine (PA) metabolism genes were overexpressed in high-risk, Thi HPV⁺ HNSCs. Genes involved in PA biosynthesis and transport were associated with T-cell infiltration, recurrent or persistent cancer, overall survival status, primary site, molecular subtype, and MYC genomic alterations. PA biogenesis gene sets were associated with tumor-intrinsic features while myeloid cells in HPV⁺ HNSCs were enriched in PA catabolism, regulatory, transport, putrescine, and spermidine gene set expression. PA gene set expression also correlated with IFNγ or cytotoxic T-cell single-sample gene set enrichment analysis (ssGSEA) scores across TCGA tumor types. PA transport ssGSEA scores were associated with poor survival whereas putrescine ssGSEA scores portended better survival for several tumor types. Thi melanomas enriched in PA synthesis or combined gene set expression exhibited worse anti-PD-1 responses. These data address hurdles to antitumor immunity warranting further investigation of divergent PA metabolism in the TME. Significance: Despite the presence of tumor-infiltrating lymphocytes and antigen, antitumor immunity is often insufficient in tumor control. We leverage HPV-related head and neck cancers to identify metabolic challenges to antitumor immune responses. PA metabolism is associated with tumor-intrinsic features while the myeloid compartment exhibits enriched PA regulatory gene expression.