Molecular signatures of T cells targeting bone marrow cancers
Description
T cell receptors (TCRs) play a pivotal role in orchestrating cellular immunity in health and disease. Endogenous or synthetically amplified T cell responses can either control or eliminate tumors. Although frequent clinical responses to immunotherapy and stem cell transplantation have been observed in hematological cancers, the antigen specificities and phenotypes of tumor reactive TCRs have not been characterized in these largely low immunogenic entities. Here, we have addressed this issue by developing and applying a multiplexed optical barcoding workflow for TCR specificity. It allows for rapid profiling of single bone marrow-resident T cells and mapping of TCR specificity to the original cell state in situ. We found that non-tumor reactive clones were either CD4+ or enriched for viral specificities, while tumor reactive T cells demonstrated clonal expansion and acquired an effector-memory phenotype. The tumor reactivity state was associated with a gene expression signature that diverges from lymphocytes infiltrating solid tumors and included CD29, which we identified as an indicator of antigen-specific T cell homing. Our approach further enabled the predictive identification tumor controlling TCRs in two patient cohorts undergoing autologous stem cell transplantation and bispecific antibody treatment, respectively. These data suggest clinically relevant endogenous anti-tumor reactivity in a subset of bone marrow-resident T cells and provide the rationale for monitoring and engineering tumor reactive T cell responses to target hematological cancers. The platform established here further allows for the antigen-agnostic identification of tumor-reactive TCRs with therapeutic potential.