Molecular signatures of T cells targeting multiple myeloma

Immunotherapeutic approaches including cell therapy are believed to be the next generation of paradigm-changing treatment options in hematological malignancies. Cell therapy using CAR-T cells or expanded autologous T cells (TILs) has shown promising results in non-solid and solid malignancies. However, acquired resistance to immunotherapy or rapid disease progression represent major clinical challenges in hematological cancers. Transgenic T cell receptors (TCRs) redirect patient-autologous lymphocytes to tumor antigens and can induce regression of refractory solid tumors. However, a bone fide population of myeloma reactive TCRs has yet to be identified. Here, we have established a multiplexed optical barcoding assay that allows for ex vivo profiling of single bone marrow-resident T cells in order to identify sequences and transcriptional signatures of patient-individual tumor-reactive lymphocytes. By integrating antigen specificity and the transcriptional profile of single myeloma-associated T cells using the CDR3 sequence as clone-specific barcode, we found that tumor-reactivity results in a specific gene expression state of bone marrow-resident CD8+ T cells. Non-tumor-reactive clones were either CD4+ or enriched for viral specificities, while myeloma reactive TCRs demonstrated an increased clonality within the overall lymphocyte repertoire. We furthermore describe a subset of CD29 (ITGB1)-expressing effector-memory CD8+ T cells that is associated with response to induction immunochemotherapy. Our results demonstrate antitumor reactivity in a subset of bone marrow-resident T cells against malignant plasma cells and provide the rationale for future personalized TCR-transgenic cell therapy approaches in newly diagnosed multiple myeloma patients. More broadly, the generated resources from this project might contribute to identifying and monitoring tumor reactive T cell responses targeting hematological neoplasias.