Aged-induced increases in IL-11 leads to immune escape and PD-1 resistance in melanoma through myeloid cell polarization

Background: Stress-like states, associated with hypoxia, drug treatment and aging, can contribute to immune escape in cancer through mechanisms that remain poorly understood. IL-11 is a poorly studied cytokine whose expression increases with age. In previous work, we have identified histone deacetylase (HDAC)-8, as an epigenetic regulator whose expression increases in response to multiple stresses. Here, we identify HDAC8 as a regulator of IL-11 expression, leading to immune escape and immunotherapy resistance in melanoma. < strong>Objectives: We investigated the role of IL-11 in modulating the immune microenvironment and its impact on melanoma progression and resistance to immunotherapy in young vs aged mice. Methods: Intrinsically sensitive and resistant melanoma cells were assayed for cytokine secretion by cytokine arrays and ELISAs. Chromatin accessibility, histone modifications, and transcriptional changes of IL-11 were assessed in human melanoma cells overexpressing HDAC8 using ATAC-seq, ChIP-seq, and scRNA-seq. ELISA, immunohistochemistry (IHC), and flow assays were employed to evaluate IL-11 expression and its effects on myeloid-derived suppressor cells (MDSCs) and T cell interactions in young vs aged mice. Young (<3M) and old (>18M) mice were treated with an IL-11 blocking antibody and/or anti-PD-1 antibody to determine drug efficacy. TMAs and IHCS from patients were stained for IL-11. Results: IL-11 expression was upregulated in melanoma cells in response to hypoxia as well as intrinsic and acquired targeted therapy treatment. Expression of IL-11 accelerated melanoma growth in vivo and led to increased accumulation of PMN-MDSCs and reduced CD8+ T cell infiltration. IL-11 expression reduced the efficacy of anti-PD-1 therapy in melanoma models, whereas IL-11 blockade enhanced anti-PD-1 responses. Old mice (>18M) had increased circulating levels of IL-11 levels compared to young mice (<3M), as well as increased IL-11 expression in the liver. Therapeutic blockade of IL-11 led to complete anti-tumor responses to anti-PD-1 in aged mice with melanomas. In melanoma patient samples, IL-11 expression was correlated with increased age, and was spatially expressed in areas of the tumor that had reduced CD8+ T cell infiltrate. Conclusions: IL-11 promotes a "cold" immune microenvironment in aged mice by increasing accumulation of PMN-MDSCs and suppressing T cell recognition and infiltration. Blocking IL-11 in aged mice contributed to increased immunotherapy efficacy. Targeting IL-11 represents a promising therapeutic strategy to limit immune escape and boost responses to anti-PD-1 in melanoma, particularly in aged patients.