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Published on: November 28, 2019
Warburg Effect Is a Cancer Immune Evasion Mechanism Against Macrophage Immunosurveillance
Jing Chen1, Xu Cao1, Bolei Li1
1Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
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.
Insights
Cancer cells evade immune detection using "don't eat me" signals and extracellular acidification. Targeting proton pumps and acidity can restore macrophage-mediated cancer cell destruction, offering new immunotherapy strategies.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Cancer cells evade immune surveillance through mechanisms like "don't eat me" signals, such as CD47, which inhibit phagocytosis by macrophages.
- While CD47 blockade shows therapeutic promise, other cancer cell self-protection strategies against macrophage surveillance remain largely unknown.
Purpose of the Study:
- To identify and characterize novel self-protective mechanisms employed by cancer cells against macrophage surveillance, independent of CD47.
- To investigate the role of extracellular acidification, driven by the Warburg effect, in conferring immune evasion to cancer cells.
- To explore therapeutic strategies targeting extracellular acidification to enhance macrophage-mediated cancer cell clearance.
Main Methods:
- Generation of a macrophage-resistant cancer model from CD47-deficient cells using a macrophage selection assay.
- Comparative analysis of parental and resistant cells to identify CD47-independent protective traits.
- In vitro phagocytosis assays and in vivo tumor models utilizing pharmacological and genetic approaches to assess the role of extracellular acidification.
Main Results:
- Extracellular acidification, a result of cancer cell glycolysis (Warburg effect), was identified as a key mechanism protecting cancer cells from macrophage phagocytosis.
- An acidic tumor microenvironment was shown to directly impair macrophage phagocytic capacity and alter macrophage polarization towards less phagocytic phenotypes.
- Targeting V-ATPase, a proton transporter, reversed tumor acidity, promoted a pro-phagocytic environment, increased M1/M2 macrophage ratios, and inhibited tumor growth and metastasis.
- Blocking extracellular acidification increased CD71 surface expression, making cancer cells more susceptible to antibody-mediated phagocytosis.
Conclusions:
- Extracellular acidification, driven by the Warburg effect, is a significant contributor to cancer immune evasion by inhibiting macrophage surveillance.
- Targeting components of the Warburg effect, specifically proton transport and extracellular acidification, represents a promising novel immunotherapy approach.
- This strategy aims to re-sensitize cancer cells to macrophage-mediated phagocytosis and harness the immune system's tumoricidal potential.
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