Prediction of immunotherapy efficacy and immunomodulatory role of hypoxia in colorectal cancer

Abstract

Immunotherapy has been used in the clinical treatment of colorectal cancer (CRC); however, most patients fail to achieve satisfactory survival benefits. Biomarkers with high specificity and sensitivity are being increasingly developed to predict the efficacy of CRC immunotherapy. In addition to DNA alteration markers, such as microsatellite instability/mismatch repair and tumor mutational burden, immune cell infiltration and immune checkpoints (ICs), epigenetic changes and no-coding RNA, and gut microbiomes all show potential predictive ability. Recently, the hypoxic tumor microenvironment (TME) has been identified as a key factor mediating CRC immune evasion and resistance to treatment. Hypoxia-inducible factor-1α is the central transcription factor in the hypoxia response that drives the expression of a vast number of survival genes by binding to the hypoxia response element in cancer and immune cells in the TME. Hypoxia regulates angiogenesis, immune cell infiltration and activation, expression of ICs, and secretion of various immune molecules in the TME and is closely associated with the immunotherapeutic efficacy of CRC. Currently, various agents targeting hypoxia have been found to improve the TME and enhance the efficacy of immunotherapy. We reviewed current markers commonly used in CRC to predict therapeutic efficacy and the mechanisms underlying hypoxia-induced angiogenesis and tumor immune evasion. Exploring the mechanisms by which hypoxia affects the TME will assist the discovery of new immunotherapeutic predictive biomarkers and development of more effective combinations of agents targeting hypoxia and immunotherapy.

Keywords: colorectal cancer; hypoxia; immune checkpoint inhibitors; immunotherapy; tumor microenvironment.

Figure 1.

ICIs for CRC. Pembrolizumab and nivolumab combined with PD-1 to block the binding of PD-1 and PD-L1/PD-L2-mediated immune escape, while ipilimumab mainly blocked the binding of CTLA-4 and increased binding of CD28 to CD80/CD86 on the surface of APCs and T cells. APC, antigen-presenting cell; CD, cluster of differentiation; CRC, colorectal cancer; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; ECM, extracellular matrix; NK cell, natural killer cell; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; PD-L2, programmed cell death-ligand 2; T cell, T lymphocyte; Treg cell, regulatory T cell.

Figure 2.

Hypoxia-induced angiogenesis and immune evasion via HIF-1α in CRC. HIF-1α is elevated by hypoxia and other molecules. After heterodimerization with HIF-1β, HIF-1α binds to HRE and activates transcription of VEGF, COX-2, TRAF6, MEF2D, and the production of exosomes containing Wnt4. These molecules directly or indirectly mediate disordered angiogenesis in TME and mediated immune evasion induced by hypoxia. COF1, cofilin 1; COX-2, cyclooxygenase-2; CRC, colorectal cancer; CXCL, C-X-C motif chemokine; CXCR, C-X-C receptor; DKC1, dyskeratosis congenita 1; HIF-1α, hypoxia-inducible factor 1α; HRE, hypoxia response element; LRG1, leucine-rich-alpha-2-glycoprotein 1; MEF2D, myocyte enhancer factor 2D; NF-κB, nuclear factor-kappa B; PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; PGE2, prostaglandin E2; PHD, prolyl hydroxylase; pVHL, Von Hippel-Lindau tumor suppressor protein; TIM-3, T-cell immunoglobulin-3; TRAF6, tumor necrosis factor receptor-associated factor 6; VEGF, vascular endothelial growth factor.

Figure 3.

Effects of hypoxia on immunosuppressive cells in CRC. Hypoxia can influence multiple aspects of immunosuppressive cells. Generally, hypoxia can induce immune tolerance and immune escape by supporting survival, migration, and functions of immunosuppressive cells (Tregs, MDSCs, and TAMs), and causing an increase in the production of immunosuppressive cytokines. Arg1, arginase 1; CSF2, colony-stimulating factor 2; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCL, C-X-C motif chemokine; FoxO1, forkhead box O1; FoxP3, forkhead box P3; GM-Exo, a G-MDSC exosome; iNOS, inducible nitric oxide synthase; IL, interleukin; MHC, major histocompatibility complex; PD-L1, programmed death ligand 1; PTTG3P, pituitary tumor-transforming 3, pseudogene; Rab27a, a GTPase required for exosome secretion; TGF, transforming growth factor; TRIB3, tribbles pseudokinase 3; VEGFR, vascular endothelial growth factor receptor; VISTA, V-domain Ig suppressor of T-cell activation.

Figure 4.

Effects of hypoxia on immunoeffector cells in CRC. Hypoxia leads to immune evasion of CRC by inhibiting infiltration, activation, maturation, and function of immune effector cells and antigen-presenting cells through multiple pathways. ADO, adenosine; CCR, CC chemokine receptor; CXCL, C-X-C motif chemokine; HIF-1α, hypoxia-inducible factor 1α; IFN, interferon; IL, interleukin; MICA, MHC class I chain-related protein A; NF-κB, nuclear factor-kappa B; NKG2D, natural killer group 2D; NKp46, natural killer cell p46-related protein; NKp30, natural killer cell p30-related protein; NKp44, natural killer cell p44-related protein; OPN, osteopontin; PTTG3P, pituitary tumor-transforming 3, pseudogene; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

Figure 5.

Effects of hypoxia on the alteration of ICs in CRC. Hypoxia induces the expression of multiple ICs (PD-L1, HLA-G, and VISTA) in the TME of CRC through the binding of HIF-1α to HRE. Hypoxia can also induce CAFs to secrete exosome circEIF3K to promote PD-L1 stability. These ICs promote the immune evasion of CRC. CAFs, cancer-associated fibroblasts; INF, interferon; HIF-1α, hypoxia-inducible factor 1α; HLA, human leukocyte antigen; PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; PKM2, pyruvate kinase isoform M2; TNF, tumor necrosis factor; VISTA, V-domain Ig suppressor of T-cell activation.