Abstract
Each year, more than 700,000 people undergo cancer surgery in the United States. However, more than 40% of those patients develop recurrences and have a poor outcome. Traditionally, the medical community has assumed that recurrent tumors arise from selected tumor clones that are refractory to therapy. However, we found that tumor cells have few phenotypical differences after surgery. Thus, we propose an alternative explanation for the resistance of recurrent tumors. Surgery promotes inhibitory factors that allow lingering immunosuppressive cells to repopulate small pockets of residual disease quickly. Recurrent tumors and draining lymph nodes are infiltrated with M2 (CD11b(+)F4/80(hi)CD206(hi) and CD11b(+)F4/80(hi)CD124(hi)) macrophages and CD4(+)Foxp3(+) regulatory T cells. This complex network of immunosuppression in the surrounding tumor microenvironment explains the resistance of tumor recurrences to conventional cancer vaccines despite small tumor size, an intact antitumor immune response, and unaltered cancer cells. Therapeutic strategies coupling antitumor agents with inhibition of immunosuppressive cells potentially could impact the outcomes of more than 250,000 people each year.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Differentiation / immunology
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Antigens, Differentiation / metabolism
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CD11b Antigen / immunology
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CD11b Antigen / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cancer Vaccines / immunology*
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Cell Line, Tumor
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Disease Models, Animal
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Female
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Flow Cytometry
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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Humans
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Interleukin-4 Receptor alpha Subunit / immunology
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Interleukin-4 Receptor alpha Subunit / metabolism
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Kaplan-Meier Estimate
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Lectins, C-Type / immunology
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Lectins, C-Type / metabolism
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Macrophages / immunology
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Macrophages / metabolism
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Male
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Mannose Receptor
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Mannose-Binding Lectins / immunology
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Mannose-Binding Lectins / metabolism
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Mice
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Mice, Inbred C57BL
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Neoplasm Recurrence, Local / immunology*
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Neoplasms / immunology*
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Neoplasms / pathology
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Neoplasms / surgery
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Receptors, Cell Surface / immunology
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Receptors, Cell Surface / metabolism
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Treatment Failure
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Tumor Microenvironment / immunology*
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Vaccination / methods
Substances
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Antigens, Differentiation
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CD11b Antigen
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Cancer Vaccines
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-4 Receptor alpha Subunit
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Lectins, C-Type
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Mannose Receptor
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Mannose-Binding Lectins
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Receptors, Cell Surface
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monocyte-macrophage differentiation antigen