Inverse relationship between oligoclonal expanded CD69- TTE and CD69+ TTE cells in bone marrow of multiple myeloma patients

CD8(+)CD57(+) terminal effector T (T-TE) cells are a component of marrow-infiltrating lymphocytes and may contribute to the altered immune responses in multiple myeloma (MM) patients. We analyzed T-TE cells in the bone marrow (BM) and peripheral blood (PB) of age-matched controls and patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed (ND) MM using flow cytometry, mass cytometry, and FlowSOM clustering. T-TE cells are heterogeneous in all subjects, with BM containing both CD69(-) and CD69(+) subsets, while only CD69(-) cells are found in PB. Within the BM-T-TE compartment, CD69(-) and CD69(+) cells are found in comparable proportions in controls, while CD69(-) cells are dominant in MGUS and SMM and predominantly either CD69(-) or CD69(+) cells in NDMM. A positive relationship between CD69(+)T(TE) and CD69(-)T(TE) cells is observed in the BM of controls, lost in MGUS, and converted to an inverse relationship in NDMM. CD69(-)T(TE) cells include multiple oligoclonal expansions of T-cell receptor/V beta families shared between BM and PB of NDMM. Oligoclonal expanded CD69(-)T(TE) cells from the PB include myeloma-reactive cells capable of killing autologous CD38(hi) plasma cells in vitro, involving degranulation and high expression of perforin and granzyme. In contrast to CD69(-)T(TE) cells, oligoclonal expansions are not evident within CD69(+)T(TE) cells, which possess low perforin and granzyme expression and high inhibitory checkpoint expression and resemble T resident memory cells. Both CD69(-)T(TE) and CD69(+)T(TE) cells from the BM of NDMM produce large amounts of the inflammatory cytokines interferon-gamma and tumor necrosis factor alpha. The balance between CD69(-) and CD69(+) cells within the BM-T-TE compartment may regulate immune responses in NDMM and contribute to the clinical heterogeneity of the disease.