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

Abstract

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 CD45RA ؊ CCR7 ؊ 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. (Blood. 2008;112:3362-3372) IntroductionMultiple myeloma (MM) is a malignant disease of bone marrow plasma cells and remains incurable with current chemotherapy regimens. [1][2][3] Although allogeneic stem cell transplantation is associated with significant morbidity and mortality, a graft-versus-myeloma effect has clearly been demonstrated, 4,5 and tumor-specific immunotherapy offers potential in the management of this disease. 6 CTAgs are a family of proteins whose expression is restricted to spermatogenic germ cells, 7 and more than 50 CTAg genes exhibit mRNA expression in testis with minimal expression in adult somatic cells. 8,9 CTAg expression is observed in a wide variety of malignancies including melanoma and epithelial tumors. T-cell tolerance to CTAg peptides appears incomplete and functional T-cell responses may be generated as a consequence of CTAg expression in tumor cells. 10 Expression of several CTAg proteins, including MAGE and NY-ESO, has been described in malignant plasma cells from patients with MM as well as transformed cell lines. [11][12][13][14][15][16][17][18] CTAg expression is detected most commonly in patients with advanced disease but is also found in a significant proportion of patients with MGUS. 15 Recently, aberrant expression of CTAgs has been shown to be a negative prognostic marker for MM 17,19 and to be associated with a proliferative subset of tumor cells. 15 There is also a correlation in MM 18 and in certain solid tumors 20 between the age of the patient and the number of expressed CTAgs. The mechanisms that underlie this expression are unclear but are at least partially related to demethylation of gene promoter sequences. 7 CTAgs have been the target for several ...

CD8+ T-cell immunity against cancer-testis antigens develops following allogeneic stem cell transplantation and reveals a potential mechanism for the graft-versus-leukemia effect

“…19 A similar pattern was observed in patient 125M with a diagnosis of MM who was initially studied more than 2 years after stem cell transplantation with a myeloablative conditioning regimen. The serum paraprotein level had risen at 124 weeks post-transplant and indicated the onset of disease relapse.…”

“…[10][11][12][13] CTAg-specific humoral and cellular immune responses have been reported in patients with a variety of solid tumors [14][15][16] and there is increasing interest in their potential role in hematopoietic malignancies. [17][18][19][20][21] CTAg may also represent an important target for the GvL effect of allogeneic transplantation and antibodies to CTAg proteins have been demonstrated in patients who have undergone stem cell transplantation for the treatment of myeloma. 21 A T-cell response to the CTAg protein NY-ESO was also observed in one patient in this cohort but this was coincident with disease relapse.…”

Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

“…Myeloma is a malignancy which is thought to be controlled, at least © F e r r a t a S t o r t i F o u n d a t i o n to a certain extent, by the adaptive immune system, a view which is supported by the fact that the therapeutic effect of allogeneic stem cell transplantation is partly mediated by donor-derived T cells and that infusions of donor T cells are capable of inducing remission in relapsed MM patients. 42,43 We and others have recently shown that spontaneous antibody and T-cell immunity against MAGE-A3 and MAGE-C1/CT7 is present in patients with MM 10,[44][45][46] and that the presence of such immunity might be associated with an improved prognosis. 44 Our finding that immune responses against CT antigens are induced by allogeneic stem cell transplantation 10 suggests that these tumor antigens might indeed represent natural targets for donor-derived allo-immune or even spontaneous anti-myeloma immune responses.…”

“…42,43 We and others have recently shown that spontaneous antibody and T-cell immunity against MAGE-A3 and MAGE-C1/CT7 is present in patients with MM 10,[44][45][46] and that the presence of such immunity might be associated with an improved prognosis. 44 Our finding that immune responses against CT antigens are induced by allogeneic stem cell transplantation 10 suggests that these tumor antigens might indeed represent natural targets for donor-derived allo-immune or even spontaneous anti-myeloma immune responses. Collectively, these findings indicate that T-cell-based immunotherapies might represent one therapeutic route for effective targeting of CT antigens.…”

Cancer Stem Cells: A Review of Potential Clinical Applications

“…46 Quintarelli et al 47,48 demonstrated PRAME-specific, cytotoxic lymphocyte cytotoxicity against chronic myelogenous leukemia cells. Goodyear et al 49 demonstrated the presence of CD8 þ , CTA-specific, cytotoxic lymphocytes in patients with MM, which, although the lymphocytes were unable to control tumor cell growth in vivo, lysed MM cells in vitro. Furthermore, patients with evidence of a CTA-specific immune response had a 53% reduction in mortality during a median follow-up of 4 years.…”