High-dimensional analysis of the CD8⁺ T cell response in multiple myeloma

Multiple myeloma is a progressive plasma cell malignancy within the bone marrow. Newly developed immunotherapies using CAR-T cells, monoclonal antibodies, and bispecific T cell engagers have led to efficacious tumor regression and have even induced remission. However, disease relapse remains high demonstrating the need for further development of effective and targeted treatments. CD8⁺ T cells play a crucial role in tumor elimination however the tumor-specific CD8⁺ T cell response in multiple myeloma is poorly defined. Here we present a high-dimensional analysis and high-throughput antigen-specificity profiling of CD8⁺ T cells of two cohorts of refractory multiple myeloma patients treated with an immunomodulator and bispecific T cell engager respectively. We screened hundreds of potential neoantigens and cancer-testis antigens across all three class I alleles and performed ex vivo scRNA-seq and CITE-Seq against both PBMC’s and TIL’s. We find cancer-testis antigen-specific CD8 T cells populations exist in a significant fraction of patients and are highly expanded within the repertoire. Tumor-infiltrating CD8⁺ T cells specific to the tumor exhibited impaired cytotoxicity, whereas following immunomodulation, these CD8⁺ T cell populations expanded in the blood and predominantly displayed a conserved highly cytotoxic phenotype. Altogether, we show reinvigoration of the tumor-specific CD8⁺ T cell response represents a promising immunotherapy against multiple myeloma.