Hypoxia and acidosis: immune suppressors and therapeutic targets

Damgaci, Sultan; Ibrahim‐Hashim, Arig; Enríquez-Navas, Pedro M.; Pilon‐Thomas, Shari; Güveniş, Albert; Gillies, Robert J.

doi:10.1111/imm.12917

Cited by 162 publications

(130 citation statements)

References 97 publications

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“…By lowering the pH in the tumor environment, lactic acid induces metabolic "dormancy" but also tumor survival in a nutrient and oxygen-deprived environment by its pro-angiogenic and antioxidant action (34 -38). Last but not least, lactic acid is involved in tumor immune response (39,40). Our own data show that the reduction of tumor lactic acid by silencing LDHA reactivated the immune response by T and NK cells (12).…”

Section: Ldha/b-dko Abolishes the Warburg Effect But Not Tumor Growthmentioning

confidence: 83%

Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism

Ždralević

Brand

Ianni

et al. 2018

Journal of Biological Chemistry

168

137

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Increased glucose consumption distinguishes cancer cells from normal cells and is known as the "Warburg effect" because of increased glycolysis. Lactate dehydrogenase A (LDHA) is a key glycolytic enzyme, a hallmark of aggressive cancers, and believed to be the major enzyme responsible for pyruvate-to-lactate conversion. To elucidate its role in tumor growth, we disrupted both the and genes in two cancer cell lines (human colon adenocarcinoma and murine melanoma cells). Surprisingly, neither nor knockout strongly reduced lactate secretion. In contrast, double knockout (-DKO) fully suppressed LDH activity and lactate secretion. Furthermore, under normoxia, -DKO cells survived the genetic block by shifting their metabolism to oxidative phosphorylation (OXPHOS), entailing a 2-fold reduction in proliferation rates and compared with their WT counterparts. Under hypoxia (1% oxygen), however, suppression completely abolished growth, consistent with the reliance on OXPHOS. Interestingly, activation of the respiratory capacity operated by the-DKO genetic block as well as the resilient growth were not consequences of long-term adaptation. They could be reproduced pharmacologically by treating WT cells with an LDHA/B-specific inhibitor (GNE-140). These findings demonstrate that the Warburg effect is not only based on high LDHA expression, as both and need to be deleted to suppress fermentative glycolysis. Finally, we demonstrate that the Warburg effect is dispensable even in aggressive tumors and that the metabolic shift to OXPHOS caused by / genetic disruptions is responsible for the tumors' escape and growth.

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Section: Ldha/b-dko Abolishes the Warburg Effect But Not Tumor Growthmentioning

confidence: 83%

Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism

Ždralević

Brand

Ianni

et al. 2018

Journal of Biological Chemistry

168

137

View full text Add to dashboard Cite

show abstract

“…In addition, it provides some survival and growth advantages, including high carbon source for anabolism, rapid ATP availability to supply the energy, abundant lactic acid to increase the redox status (NADPH) via the glycine-serine pathway (6)(7)(8). Lactic acid induces metabolic "dormancy" and is involved in EMT and tumor immune response by reducing pH in the tumor environment (5,8,(23)(24)(25). To manage all the situations above, cancer cells must maintain a balance to deliver adequate energy with constrained resources and to meet the biosynthetic demands of proliferation.…”

Section: The Impact Of Glucose Metabolism On Tumor Plasticitymentioning

confidence: 99%

Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment

et al. 2020

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Malignant cells support tumor proliferation and progression by adopting to metabolic changes. Tumor cells altered metabolism by increasing glucose uptake and fermentation of glucose to lactate, even in the aerobic state and the presence of functioning mitochondria. Glucose metabolism in tumor plasticity has attracted great interests by clinicians and scientists in the past decades. This review discusses the previous and emerging researches on the tumor plasticity altered by changing glucose metabolism in different cancer cells, including cancer stem cells (CSCs). In addition, we summarize the rising applications of glucose metabolism in tumor diagnosis and treatment. Our objective is to direct future investigation on this altered metabolic phenotype and its application in patient care.

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“…Neutralization of acidity with bicarbonate within the TME or inhibiting lactate production in the tumor by reducing LDHA expression has been shown to increase immune activity and enhance the efficacy of ICB (18,19). However, these approaches lack specificity for the tumor and are faced with challenges clinically (13,20). Thus, there remains an unmet need to specifically restore pH homeostasis within the TME, while leaving the immune system unaffected.…”

Section: Introductionmentioning

confidence: 99%

Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically

Chafe¹,

McDonald²,

Saberi³

et al. 2019

Cancer Immunology Research

108

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Treatment strategies involving immune-checkpoint blockade (ICB) have significantly improved survival for a subset of patients across a broad spectrum of advanced solid cancers. Despite this, considerable room for improving response rates remains. The tumor microenvironment (TME) is a hurdle to immune function, as the altered metabolism-related acidic microenvironment of solid tumors decreases immune activity. Here, we determined that expression of the hypoxia-induced, cell-surface pH regulatory enzyme carbonic anhydrase IX (CAIX) is associated with worse overall survival in a cohort of 449 patients with melanoma. We found that targeting CAIX with the small-molecule SLC-0111 reduced glycolytic metabolism of tumor cells and extracellular acidification, resulting in increased immune cell killing. SLC-0111 treatment in combination with immune-checkpoint inhibitors led to the sensitization of tumors to ICB, which led to an enhanced Th1 response, decreased tumor growth, and reduced metastasis. We identified that increased expression of CA9 is associated with a reduced Th1 response in metastatic melanoma and basal-like breast cancer TCGA cohorts. These data suggest that targeting CAIX in the TME in combination with ICB is a potential therapeutic strategy for enhancing response and survival in patients with hypoxic solid malignancies.

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Hypoxia and acidosis: immune suppressors and therapeutic targets

Cited by 162 publications

References 97 publications

Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism

Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism

Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment

Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically

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