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Cancer Res. 2015 Aug 15;75(16):3268-78. doi: 10.1158/0008-5472.CAN-14-3640. Epub 2015 Jun 2.

Tumors Escape CD4+ T-cell-Mediated Immunosurveillance by Impairing the Ability of Infiltrating Macrophages to Indirectly Present Tumor Antigens.

Author information

1
Centre for Immune Regulation, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway. anders.tveita@medisin.uio.no.
2
Centre for Immune Regulation, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway.
3
Centre for Immune Regulation, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway. KG Jebsen Centre for Influenza Vaccine Research, Institute of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway.

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.

PMID:
26038231
DOI:
10.1158/0008-5472.CAN-14-3640
[Indexed for MEDLINE]
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