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Fig. 3 | Journal of Experimental & Clinical Cancer Research

Fig. 3

From: Targeting hypoxia in the tumor microenvironment: a potential strategy to improve cancer immunotherapy

Fig. 3

The regulation of hypoxia on immune checkpoints in the TME. a Under hypoxia, the stabilization of HIF-1α upregulates the expression of PD-L1 in hypoxic tumor cells DCs, macrophages, and MDSCs. b HIF-1α is involved in the upregulation of CD47 on tumor cell surface. The binding of CD47 to SIRPα, abundantly expressed on myeloid-linage hematopoietic cells like MDSCs and TAMs, delivers a potent “don’t eat me signal” to block phagocytosis of cancer cells. c Hypoxia upregulates the expression of HLA-G on the surface of tumor cells. The upregulated HLA-G binds to its inhibitory receptors on immune cells, inducing immune suppression and promoting immune escape by interfering with DC antigen presentation, suppressor T-cell induction, and cytotoxic attack inhibition. d Hypoxia can upregulate the expression of VISTA on myeloid cells, including MDSCs, macrophages, and DCs by the binding of HIF-1α to the HRE in VISTA promoter, suppressing T cell proliferation and activity. e Through HIF-1α stabilization, hypoxia upregulates the expression of inhibitory immune checkpoints (LAG-3 and CTLA4) and the co-stimulatory factors (CD137and OX40) on the surface of T cells, and decreased co-stimulatory molecules like CD40, CD80, and CD86 expressed on the surface of DCs

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