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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3362-3372.
Prepublished online as a Blood First Edition Paper on July 24, 2008; DOI 10.1182/blood-2008-04-149393.


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NEOPLASIA

Differential pattern of CD4+ and CD8+ T-cell immunity to MAGE-A1/A2/A3 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma

Oliver C. Goodyear1, Guy Pratt1, Andrew McLarnon1, Mark Cook2, Karen Piper1, and Paul Moss1

1 Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham; and 2 Department of Haematology, University Hospital Birmingham National Health Service (NHS) Trust, Birmingham, United Kingdom

The factors that determine progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma are unclear but may include the breakdown of immune surveillance. Cancer testis antigens (CTAgs) are expressed by the majority of myelomas and MGUS tumors and are a potential immune target. We have characterized CD4+ and CD8+ T-cell immune responses to MAGE-A1/A2/A3 in these patients. CD4+ T-cell immunity to MAGE proteins is stronger and more frequent in MGUS compared with myeloma with a predominantly CD45RACCR7 effector memory profile and cytotoxicity against MAGE-positive cell lines. In contrast CD8+ T-cell immune responses were present almost exclusively in patients with multiple myeloma, correlating with disease, with a CD45RA+CCR7 memory phenotype, localizing poorly to the bone marrow but were able to lyse myeloma cell lines in vitro. This suggests that the CD4+ CTAg-specific immune response may play a role in controlling tumor growth, whereas the efficacy of the CD8+ T-cell response appears to be limited in vivo. Despite this, patients with evidence of a CTAg-specific immune response had a 53% reduction in mortality over a median follow-up of 4 years. These findings have important implications for clinical approaches to CTAg-specific immunotherapy in patients with cancer.


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