Warburg Effect Is a Cancer Immune Evasion Mechanism Against Macrophage Immunosurveillance

Abstract

Evasion of immunosurveillance is critical for cancer initiation and development. The expression of “don’t eat me” signals protects cancer cells from being phagocytosed by macrophages, and the blockade of such signals demonstrates therapeutic potential by restoring the susceptibility of cancer cells to macrophage-mediated phagocytosis. However, whether additional self-protective mechanisms play a role against macrophage surveillance remains unexplored. Here, we derived a macrophage-resistant cancer model from cells deficient in the expression of CD47, a major “don’t eat me” signal, via a macrophage selection assay. Comparative studies performed between the parental and resistant cells identified self-protective traits independent of CD47, which were examined with both pharmacological or genetic approaches in in vitro phagocytosis assays and in vivo tumor models for their roles in protecting against macrophage surveillance. Here we demonstrated that extracellular acidification resulting from glycolysis in cancer cells protected them against macrophage-mediated phagocytosis. The acidic tumor microenvironment resulted in direct inhibition of macrophage phagocytic ability and recruitment of weakly phagocytic macrophages. Targeting V-ATPase which transports excessive protons in cancer cells to acidify extracellular medium elicited a pro-phagocytic microenvironment with an increased ratio of M1-/M2-like macrophage populations, therefore inhibiting tumor development and metastasis. In addition, blockade of extracellular acidification enhanced cell surface exposure of CD71, targeting which by antibodies promoted cancer cell phagocytosis. Our results reveal that extracellular acidification due to the Warburg effect confers immune evasion ability on cancer cells. This previously unrecognized role highlights the components mediating the Warburg effect as potential targets for new immunotherapy harnessing the tumoricidal capabilities of macrophages.

Dual Role of p73 in Cancer Microenvironment and DNA Damage Response

“…The later stages of cancer are associated with well-known cancer hallmarks [ 86 ] including induction of angiogenesis to feed the growth of cancer cells [ 87 , 88 ], activation of metastasis driven by the epithelial-to-mesenchymal transition (EMT) [ 89 , 90 , 91 ], evasion from the immune surveillance, and formation of the tumor microenvironment [ 92 , 93 , 94 , 95 , 96 , 97 ].…”

Prognostic Value of a Glycolytic Signature and Its Regulation by Y-Box-Binding Protein 1 in Triple-Negative Breast Cancer

“…Aberrant glycolysis is commonly associated with proinflammatory responses and immune evasion in the TME [37,44]. Recent studies showed that YBX1 regulated programmed death ligand 1 (PD-L1) expression to mediate immune escape in prostate cancer [45], and the infiltrating cluster of differentiation 4-positive (CD4+) T cells promoted the growth of renal cell carcinoma via modulating transforming growth factor-β1 (TGFβ1)/YBX1/HIF2α signals [46].…”

Novel possibility for cutaneous melanoma treatment by means of rosmarinic acid action on purinergic signaling

“…Diverse evidence suggests that the immune cells' response in the TME contributes to cancer cell survival and growth [49]. Interestingly, this abnormal metabolic profile has been pointed out as one of the factors which support immune evasion to tumor cells and promote tumor progression [50][51][52][53]. What justified this fact is that, as cytoplasmic is produced, lactate is released in the extracellular microenvironment by monocarboxylate transporters (MCTs), leading to pH reduction and to TME acidification [54,55].…”