Association of Antigen-Specific T-cell Responses with Antigen Expression and Immunoparalysis in Multiple Myeloma

Abstract

Purpose: Cancer testis antigens (CTA) are immunotherapeutical targets aberrantly expressed on multiple myeloma cells, especially at later stages, when a concomitant immunoparesis hampers vaccination approaches. Experimental Design: We assessed the expression of the multiple myeloma antigen HM1.24 (reported present in all malignant plasma cells) and the CTAs MAGE-A2/A3 and NY-ESO-1 (aberrantly expressed in a subset of patients with myeloma), in CD138-purified myeloma cells by qRT-PCR (n = 149). In a next step, we analyzed the antigen-specific T-cell responses against these antigens by IFNγ EliSpot assay (n = 145) and granzymeB ELISA (n = 62) in relation to stage (tumor load) and expression of the respective antigen. Results: HM1.24 is expressed in all plasma-cell samples, whereas CTAs are significantly more frequent in later stages. HM1.24-specific T-cell responses, representing the immunologic status, significantly decreased from healthy donors to advanced disease. For the CTAs, the probability of T-cell responses increased in early and advanced stages compared with healthy donors, paralleling increased probability of expression. In advanced stages, T-cell responses decreased because of immunoparesis. Conclusion: In conclusion, specific T-cell responses in myeloma are triggered by antigen expression but suppressed by tumor load. Future CTA-based immunotherapeutical approaches might target early plasma-cell diseases to establish prophylactically a specific T-cell response against late-stage antigens in immunocompetent patients. Clin Cancer Res; 21(7); 1712–21. ©2015 AACR.

Frequency of expression and generation of T-cell responses against antigens on multiple myeloma cells in patients included in the GMMG-MM5 trial

“…This potentially also explains the high variability in reported frequencies of NY-ESO-1 expression [ 24 , 38 , 39 ]. The reported frequencies here are however in agreement with detected frequencies of NY-ESO-1 expression previously found by us using qRT-PCR [ 2 ].…”

“…However, it is unlikely that this is due to lack of sensitivity regarding detection. First, we had previously shown immune response against CTAs to be detectable despite absence of antigen expression in malignant plasma cells by quantitative real-time PCR [ 2 ]. We confirm this here using a different method (GEP) and the additional antigens HMMR and WT-1.…”

“…Lack of T-cell responses despite target expression is less difficult to understand as one of the most prominent effects of accumulation of malignant plasma cells in myeloma is induction of immunosuppression visible in dysfunctional DCs and diminished T-cell activation [ 2 – 4 ]. Potential circumvention of this effect is augmenting immune response by adding immunomodulatory drugs like IMiDs [ 42 , 43 ], or using vaccination approaches at earlier stages e.g.…”

“…Multiple myeloma is characterized by the accumulation of clonal plasma cells in the bone marrow and associated clinical signs and symptoms, especially those related to the displacement of normal hematopoiesis, generation of osteolytic bone disease, and production of a monoclonal protein [ 1 ]. One of the most prominent effects thereof is the induction of immunosuppression visible in dysfunctional dendritic cells (DC) and diminished T-cell activation [ 2 – 4 ]. In turn, immunotherapeutic approaches to eliminate myeloma cells by fostering host immunity are in development.…”

A transplant “immunome” screening platform defines a targetable epitope fingerprint of multiple myeloma

“…25,[43][44][45][46] Here, we profiled epitope recognition in a cohort of 18 patients after allogeneic or autologous HSCT or novel agent therapy, revealing strikingly disease-specific and overlapping patterns of epitope reactivity. All of these patients showed oligoclonal serum antibodies on immunofixation, suggesting ongoing B-cell immune responses.…”