The aged tumor microenvironment limits T cell control of cancer.

The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8+ T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8+ T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (TTAD) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8+ T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes TTAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8+ T cell immunity in aging.

Interferon regulatory factor 4 modulates epigenetic silencing and cancer-critical pathways in melanoma cells.

Interferon regulatory factor 4 (IRF4) was initially identified as a key controller in lymphocyte differentiation and function, and subsequently as a dependency factor and therapy target in lymphocyte-derived cancers. In melanocytes, IRF4 takes part in pigmentation. Although genetic studies have implicated IRF4 in melanoma, how IRF4 functions in melanoma cells has remained largely elusive. Here, we confirmed prevalent IRF4 expression in melanoma and showed that high expression is linked to dependency in cells and mortality in patients. Analysis of genes activated by IRF4 uncovered, as a novel target category, epigenetic silencing factors involved in DNA methylation (DNMT1, DNMT3B, UHRF1) and histone H3K27 methylation (EZH2). Consequently, we show that IRF4 controls the expression of tumour suppressor genes known to be silenced by these epigenetic modifications, for instance cyclin-dependent kinase inhibitors CDKN1A and CDKN1B, the PI3-AKT pathway regulator PTEN, and primary cilium components. Furthermore, IRF4 modulates activity of key downstream oncogenic pathways, such as WNT/ß-catenin and AKT, impacting cell proliferation and survival. Accordingly, IRF4 modifies the effectiveness of pertinent epigenetic drugs on melanoma cells, a finding that encourages further studies towards therapeutic targeting of IRF4 in melanoma.