Altered Immunogenicity of Proteasome Inhibitor-Resistant Myeloma Cells in the 5T33MM Model 9271

Abstract Description Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells that remains incurable. Proteasome inhibitors (PIs) have significantly improved MM patient survival, but drug resistance limits their efficacy. PI-resistant MM cells are generally considered less immunogenic than sensitive cells, but their immunogenicity and associated anti-tumor immune responses are not fully understood. Here, bortezomib (BTZ)-resistant murine 5T33MM (5T33MM-BTZ-R) cells were established by exposure to increasing concentrations of BTZ. Interestingly, 5T33MM-BTZ-R tumor growth was significantly suppressed in immunocompetent syngeneic C57BL/KaLwRij mice, whereas BTZ-sensitive 5T33MM (5T33MM-BTZ-S) tumors exhibited rapid growth. In contrast, both 5T33MM-BTZ-R and 5T33MM-BTZ-S tumors grew similarly in nude mice lacking T cells. Additionally, tumor growth of carfilzomib- and ixazomib-resistant 5T33MM cells was also suppressed in immunocompetent mice. Furthermore, tumor growth of 5T33MM-BTZ-S was significantly suppressed in mice previously challenged with 5T33MM-BTZ-R. Adoptive transfer revealed that memory T cells from 5T33MM-BTZ-R-challenged mice suppressed 5T33MM-BTZ-S tumor growth in syngeneic mice. Cytokine analysis showed increased IL-12 and CXCL2/MIP-2 production by 5T33MM-BTZ-R cells. Together, these findings suggest a potential strategy for overcoming MM drug resistance and designing novel immunotherapeutic approaches. Funding Sources Supported by NIH/NCI R03CA259901; NIH P30CA043703; I’m Not Done Yet Foundation; Center for Pediatric Immunotherapy at Rainbow. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)