Warburg Effect Is a Cancer Immune Evasion Mechanism Against Macrophage Immunosurveillance
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 o...
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| Published in: | Frontiers in immunology Vol. 11; p. 621757 |
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| Main Authors: | , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Switzerland
Frontiers Media S.A
02-02-2021
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | 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,
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
phagocytosis assays and
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. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors have contributed equally to this work This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology Edited by: Johnathan Canton, Francis Crick Institute, United Kingdom Reviewed by: Raymond B. Birge, Rutgers, The State University of New Jersey, United States; Jaime F. Modiano, University of Minnesota Twin Cities, United States |
| ISSN: | 1664-3224 1664-3224 |
| DOI: | 10.3389/fimmu.2020.621757 |