Utilizing an immune- and proliferation-depleted gene set that defined “stemness”, and data from TCGA, Miranda and Hamilton et al. performed an integrated analysis of 8,290 tumors across 21 solid tumor types. Tumor stemness varied across cancer types and was predictive of poor patient survival. Stemness negatively correlated with immune infiltration, type I IFN signaling, and endogenous retrovirus expression, and positively correlated with tumor heterogeneity, mutation load, expression of cancer testis antigen, and immunosuppression, supporting a hypothesis that stemness promotes immune evasion, resulting in cold TMEs that foster heterogeneity.
Regulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype ("stemness") on the immunological properties of cancer has not been systematically explored. Using gene-expression-based metrics, we evaluated the association of stemness with immune cell infiltration and genomic, transcriptomic, and clinical parameters across 21 solid cancers. We found pervasive negative associations between cancer stemness and anticancer immunity. This occurred despite high stemness cancers exhibiting increased mutation load, cancer-testis antigen expression, and intratumoral heterogeneity. Stemness was also strongly associated with cell-intrinsic suppression of endogenous retroviruses and type I IFN signaling, and increased expression of multiple therapeutically accessible immunosuppressive pathways. Thus, stemness is not only a fundamental process in cancer progression but may provide a mechanistic link between antigenicity, intratumoral heterogeneity, and immune suppression across cancers.