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    • Interestingly hypoxia and an enhanced Warburg effect ultimat

    2023-01-27

    Interestingly, hypoxia and an enhanced Warburg effect ultimately lead to increased lactate production. The accumulation of lactate results in an acidic tumor microenvironment, which induces local inflammation. Lactate also promotes the polarization of macrophages that express immunosuppressive arginase 1 and boost tumor growth through a mechanism mediated by HIF-1α [33]. Attracted immune Pyr3 australia then promote immune suppression, providing an opportunity for tumor cell proliferation 34, 35. Thus, changes in the tumor microenvironment resulting from metabolic alterations attract immune cells and modulate their function, suppressing tumor-specific immunity and facilitating tumor proliferation. Physiological conditions other than hypoxia can also activate HIF-1α in immune cells associated with GBM pathogenesis. For example, the activation of CD4+ T helper 17 (Th17), CD4+ type 1 Tregs (Tr1 cells) and CD8+ T cells (cytotoxicT lymphocytes, CTLs) results in HIF-1α stabilization in an oxygen-independent manner 6, 63, 64, 65, 66. In these cells, HIF-1α signaling is thought to reflect the activation of mTORc1 66, 67. The stabilization of HIF-1α in these cells leads to increased glycolysis, which supports the metabolic requirements of proliferating cells following their stimulation. For example, Finlay et al. showed that the HIF-1α pathway sustains the expression of several genes that control glycolysis and pyruvate metabolism in effector CD8+ T cells [67]. However, although the later stages of the glycolytic process are significantly impaired, the early processes of glycolysis are intact in the context of HIF-1α deficiency in effector CD8+ T cells [67]. Moreover, HIF-1α-deficient CD8+ T cells show reduced trafficking and expression of granzymes and perforin, indicating that HIF-1α supports cytotoxic effector responses in CTLs [67]. Supporting the involvement of HIF-1α in activating cytolytic effector molecules, CD8+ T cells cultured under hypoxic conditions upregulate perforin expression. These findings explain earlier observations demonstrating that CTLs exhibit cytotoxic activity under hypoxia [68]. Collectively, these data suggest that HIF-1α activation impacts the effector function of tumor-specific T cells. HIF-1α also influences the differentiation of helper T cell lineages that have an important role in GBM pathogenesis 63, 66. For example, HIF-1α promotes the generation, maintenance, and function of Th17 cells 63, 66, 69. In addition, HIF-1α promotes Foxp3 ubiquitination and its degradation by the proteasome in Th17 cells [63], suppressing Foxp3+ Treg differentiation. Conversely, the expression of HIF-1α is reduced under conditions promoting Foxp3+ Treg differentiation [66]. These findings suggest that aerobic glycolysis promotes Th17 cell differentiation. Indeed, the blockade of glycolysis inhibits Th17 cell generation while stimulating Foxp3+ Treg cell development [66]. Finally, HIF-1α signaling in antigen-presenting cells has been shown to modulate their ability to promote the differentiation of Th1 cells and Foxp3+ Tregs [70]. Collectively, these findings suggest that, besides its direct role in cancer cell metabolism, HIF-1α is an important factor in the control of tumor-specific immunity.
    AHR AHR has been linked to several forms of cancer, including GBM 30, 71, 72. In addition, the expression of the AHR repressor (AHRR) is downregulated due to hypermethylation in several human malignancies [73]. The regulation of AHR expression has not been well described in cancer. NF-κB, dysregulated in cancer, has been shown to activate directly the transcription of AHR in immune cells, implying its potential role in the transcriptional regulation of AHR in cancer [74]. AHR acts as a receptor for ligands provided by the diet, gut flora, metabolism, and environment. The inactive cytosolic AHR is part of a protein complex that includes the 90-kDa heat shock protein (HSP90), the c-SRC protein kinase, and the AHR-interacting protein Ara9. Ligand binding triggers conformational changes that expose a protein kinase C target site, phosphorylation of which triggers the translocation of the AHR to the nucleus and the dissociation of the AHR/HSP90/c-SRC complex. In the nucleus, AHR partners with ARNT to control the expression of target genes. AHR can also trigger nongenomic signaling pathways independent of its role as a transcription factor [45]. One of these pathways results from the release of c-SRC from the AHR/HSP90/c-SRC complex, enabling c-SRC to then target multiple cellular targets [45].