Antigen-specific T-cell Responses with Antigen-expression and Immunoparalysis in Multiple Myeloma

Running title: Antigen-expression and specific T-cell responses in Myeloma th framework program OVER-MyR. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Despite a variety of therapeutical approaches including high dose chemotherapy with subsequent autologous stem cell transplantation, Multiple Myeloma remains an almost incurable disease. New treatment options, like T-cell based immunotherapy seem to be a promising approach. In this study, we evaluate the impact of immunosuppression and antigen-expression on the development of specific CD8 + T-cell responses against myeloma associated antigens in patients with different stages of plasmacell-dyscrasias. Our analysis shows that antigen specific immunoresponses correlate with the expression of the antigen and an early stage of the disease. In conclusion, a T-cell based immunotherapy in patients with plasmacell-dyscrasias might be performed in an early stage of the disease, where the tumor associated immunosuppression is low and it might be possible to establish a prophylactic immune response against antigens that were not yet expressed. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Cancer testis antigens are immunotherapeutical targets aberrantly expressed on multiple myeloma cells, especially at later stages, when a concomitant immunoparesis hampers vaccination approaches. We assessed the expression of the multiple myeloma antigen HM1.24 (reported present in all malignant plasma-cells) and the cancer testis antigens MAGE-A2/A3 and NY-ESO-1 (aberrantly expressed in a subset of myeloma patients), 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 IFN-γ EliSpot-assay (n=145) and granzymeB ELISA (n=62) in relation to stage (tumor load) and expression of the respective antigen. HM1.24 is expressed in all plasma-cell samples, whereas cancer testis antigens are significantly more frequent in later stages. HM1.24 specific T-cell responses, representing the immunological status, significantly decreased from healthy donors to advanced disease. For the cancer testis antigens, the probability of T-cell responses increased in early and advanced stages compared to healthy donors, paralleling increased probability of expression. In advanced stages, T-cell responses decreased due to immunoparesis. In conclusion, specific T-cell responses in myeloma are triggered by antigen-expression but suppressed by tumor load. Future cancer testis antigen-based immunotherpeutical approaches might target early plasmacell-diseases to establish Research. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 4 prophylactically a specific T-cell response against late stage antigens in immunocompetent patients. …