Hallmarks of T-cell exhaustion and antigen experience are absent in multiple myeloma from diagnosis to maintenance therapy

ABSTRACT: Dysregulation of the bone marrow (BM) niche in multiple myeloma (MM) alters the composition and state of resident immune cells, potentially impeding antitumor immunity. One common mechanism of immune inhibition in solid tumors is the induction of exhaustion in tumor-specific T cells. However, the extent of T-cell exhaustion is not well characterized in MM. As the specific mechanisms of immune evasion are critical for devising effective therapeutic strategies, we deeply profiled the CD8+ T-cell compartment of patients with newly diagnosed MM (NDMM) for evidence of T-cell activation and exhaustion. We applied single-cell multiomic sequencing and mass cytometry to longitudinal BM and peripheral blood (PB) samples taken from time points spanning from diagnosis to induction therapy, autologous stem cell transplant, and maintenance therapy. We identified an exhausted-like population that lacked several canonical exhaustion markers, was not significantly enriched in patients with NDMM, and consisted of small, nonpersistent clonotypes. We also observed an activated population with increased frequency in the PB of patients with NDMM exhibiting phenotypic and clonal features consistent with homeostatic, cytokine-driven activation. As an orthogonal measurement of T-cell exhaustion, we performed intracellular cytokine staining and found that patients with NDMM lacked functionally exhausted T cells. In summary, there was no evidence of "tumor-experienced" T cells displaying hallmarks of terminal exhaustion and/or antigen-driven activation/expansion in patients with NDMM at any time point.