The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma.,Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored.,To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type‐specific genes extracted from genome‐wide methylation arrays.,Unsupervised clustering identified three immune methylation clusters with varying levels of immune CpG methylation that are related to patient survival.,Matching protein and gene expression data further corroborated the identified epigenetic characterization.,Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss‐of‐function events for melanomas unresponsive to immunotherapies (immune‐low).,To understand whether melanoma tumors resemble other solid tumors in terms of immune methylation characteristics, we explored 15 different solid tumor cohorts from TCGA.,Low‐dimensional projection based on immune cell type‐specific methylation revealed grouping of the solid tumors in line with melanoma immune methylation clusters rather than tumor types.,Association of survival outcome with immune cell type‐specific methylation differed across tumor and cell types.,However, in melanomas immune cell type‐specific methylation was associated with inferior patient survival.,Exploration of the immune methylation patterns in a pan‐cancer context suggested that specific immune microenvironments might occur across the cancer spectrum.,Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.,The importance of the tumor immune microenvironment has been highlighted in multiple cancers, but information regarding the contribution of individual immune cell types is lacking for melanoma.,In this study, we have sought to fill the gap by identifying distinct DNA methylation patterns for specifc immune cells.,These were corroborated by other molecular correlates and found to be shared across other types of solid tomors.
The presence of T cells in tumors predicts overall survival for cancer patients.,However, why most tumors are poorly infiltrated by T cells is barely understood.,T-cell recruitment towards the tumor requires a chemokine gradient of the critical IFNγ-induced chemokines CXCL9/10/11.,Here, we describe how tumors can abolish IFNγ-induced chemokines, thereby reducing T-cell attraction.,This mechanism requires extracellular galectin-3, a lectin secreted by tumors.,Galectins bind the glycans of glycoproteins and form lattices by oligomerization.,We demonstrate that galectin-3 binds the glycans of the extracellular matrix and those decorating IFNγ.,In mice bearing human tumors, galectin-3 reduces IFNγ diffusion through the tumor matrix.,Galectin antagonists increase intratumoral IFNγ diffusion, CXCL9 gradient and tumor recruitment of adoptively transferred human CD8+ T cells specific for a tumor antigen.,Transfer of T cells reduces tumor growth only if galectin antagonists are injected.,Considering that most human cytokines are glycosylated, galectin secretion could be a general strategy for tumor immune evasion.,Most tumours are poorly infiltrated by T cells.,Here the authors show that galectin-3 secreted by tumours binds both glycosylated IFNγ and glycoproteins of the tumour extracellular matrix, thus avoiding IFNγ diffusion and the formation of an IFNγ-induced chemokine gradient required for T cell infiltration.