CD4 and cancer: Aside to this direct effect of hypoxia on checkpoint inhibitory molecule expression, several studies suggest that cytotoxic T-cell proliferation and activity are severely compromised under the acidic conditions of the tumour microenvironment.10,11 In addition, chemokines produced by cancer cells under acidic and hypoxic conditions, induce chemotaxis of Tregs.33 HIF activation also seems to induce differentiation of CD4+ cells to FOXP3-expressing Tregs, either by direct binding to the FOXP3 regulatory region or by induction of TGFβ.34,35