Article ; Online: Tumors Escape CD4+ T-cell-Mediated Immunosurveillance by Impairing the Ability of Infiltrating Macrophages to Indirectly Present Tumor Antigens.
2015 Volume 75, Issue 16, Page(s) 3268–3278
Abstract: ... reinstated tumor rejection. These results show that tumors can escape CD4+ T-cell-mediated rejection ... by impairing indirect presentation of tumor antigen by infiltrating macrophages. This occurs through a novel ... Infiltrating macrophages process and present the secreted tumor antigen to Th1 cells, resulting in induction ...
| Abstract | Tumors cells can escape cytotoxic CD8+ T cells by preventing MHC I display of tumor antigens. It is unknown how tumors evade CD4+ T-cell responses, but because many tumor cells lack MHC II expression, novel mechanisms would be required. We have investigated this issue in a model in which MHC II(NEG) myeloma cells secrete a monoclonal Ig containing a V region L chain (VL) epitope recognized by CD4+ T cells. Infiltrating macrophages process and present the secreted tumor antigen to Th1 cells, resulting in induction of macrophage cytotoxicity and apparent rejection of the tumor. Despite long-term tumor protection in VL-specific T-cell receptor transgenic mice, we here describe that some myeloma cells persisted in a dormant state and, eventually, formed expanding tumors. Escape tumor cells maintained their secretion of complete (H+L) monoclonal Ig with unchanged sequence, while secretion of surplus free L chain was severely diminished. Although free L chains were efficiently processed and presented by tumor-infiltrating macrophages to CD4+ T cells, complete (H+L) monoclonal Ig was not. Forced overexpression of free L chain secretion reinstated tumor rejection. These results show that tumors can escape CD4+ T-cell-mediated rejection by impairing indirect presentation of tumor antigen by infiltrating macrophages. This occurs through a novel mechanism of immunoediting, in which modulation of the quaternary structure of the secreted tumor-specific antigen reduces its immunogenicity. |
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| MeSH term(s) | Animals ; Antigens, Neoplasm/immunology ; Antigens, Neoplasm/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival/immunology ; Female ; Immunoglobulin Light Chains/immunology ; Immunoglobulin Light Chains/metabolism ; Immunologic Surveillance/immunology ; Macrophages/immunology ; Macrophages/metabolism ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Mice, SCID ; Mice, Transgenic ; Multiple Myeloma/immunology ; Multiple Myeloma/pathology ; Survival Analysis ; Tumor Escape/immunology | |||||
| Chemical Substances | Antigens, Neoplasm ; Immunoglobulin Light Chains | |||||
| Language | English | |||||
| Publishing date | 2015-08-15 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 1432-1 | |||||
| ISSN | 1538-7445 ; 0008-5472 | |||||
| ISSN (online) | 1538-7445 | |||||
| ISSN | 0008-5472 | |||||
| DOI | 10.1158/0008-5472.CAN-14-3640 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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