The mechanisms by which HIF-1 suppresses the function of effector T-cells are complex, but include the upregulation of co-inhibitory receptors (e.g., CTLA-4 and LAG-3) [104,113], the differentiation of CD4+ T-cells into Tregs and the indirect effect of altered tumour cell metabolism [85,92]. This evidence concerns the gene CD4 and neoplasm.