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

Abstract

CD8+CD57+ terminal effector T (TTE) cells are a component of marrow-infiltrating lymphocytes and may contribute to the altered immune responses in multiple myeloma (MM) patients. We analyzed TTE 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. TTE 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-TTE 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+TTE and CD69−TTE cells is observed in the BM of controls, lost in MGUS, and converted to an inverse relationship in NDMM. CD69−TTE cells include multiple oligoclonal expansions of T-cell receptor/Vβ families shared between BM and PB of NDMM. Oligoclonal expanded CD69−TTE cells from the PB include myeloma-reactive cells capable of killing autologous CD38hi plasma cells in vitro, involving degranulation and high expression of perforin and granzyme. In contrast to CD69−TTE cells, oligoclonal expansions are not evident within CD69+TTE cells, which possess low perforin and granzyme expression and high inhibitory checkpoint expression and resemble T resident memory cells. Both CD69−TTE and CD69+TTE cells from the BM of NDMM produce large amounts of the inflammatory cytokines interferon-γ and tumor necrosis factor α. The balance between CD69− and CD69+ cells within the BM-TTE compartment may regulate immune responses in NDMM and contribute to the clinical heterogeneity of the disease.

Treg and Oligoclonal Expansion of Terminal Effector CD8+ T Cell as Key Players in Multiple Myeloma

“…Our recent research provides novel evidence supporting the idea that oligoclonal expanded T TE are key players in myeloma disease control ( 12 ). We demonstrated that oligoclonal expansions not limited to PB CD8 + T TE also occurred in CD8 + T TE which belong to the pool of marrow infiltrating lymphocytes (MILs) ( 12 ). The mechanism underlining oligoclonal expansions of T TE cells is unclear but infers reactivity against putative myeloma antigens.…”

“…Expanded oligoclonal CD8 + T TE in BM and PB share same phenotype indicative of strong cytotoxic function with high expression of perforin and granzyme B and a Tbet hi Eomes lo/neg signature ( Figure 1 ). Low expression of the inhibitory checkpoints CD279 (PD-1), TIGIT, CD223 (Lag3) and CD160, suggests that these cells may not be exhausted and thus not an appropriate or optimal target for checkpoint blockade immunotherapy ( 12 , 42 , 43 ).…”

“…This further suggests that T cells may recognize myeloma antigens and differentiate into T TE which are able to exert cytotoxicity against malignant plasma cells through perforin and granzyme expression. Until recently this possibility had not been demonstrated in an autologous setting, but the recent demonstration of cytotoxicity mediated by circulating oligoclonal expanded T TE against autologous malignant plasma cells provides proof for this concept and an opportunity to elucidate potential myeloma antigens as well as harnessing these cells for therapy ( 12 ). However, the crucial factor, or gatekeeper, which allows for BM-residency of Treg and T TE , and therefore immune surveillance at the site of malignant disease is yet to be determined.…”

Bystander Memory T Cells and IMiD/Checkpoint Therapy in Multiple Myeloma: A Dangerous Tango?

“…This is not to say that CD4 T cells are unimportant. Although reduced in some MM patients, CD8+ T central memory (Tcm) (CD45RA−,CD45RO+,CCR7+), T effector memory (Tem) (CD45RA+,CD45RO+,CCR7−) as well as T resident memory (Trm) (CD45RA–,CD45RO+,CD103+,CD69+) are found in the bone marrow ( 17 , 19 , 25 ). In addition to the markers above, memory cells also express certain transcription factors whose expression may vary according to the degree of activation and the milieu in the TME.…”

“…Some of these cells recognize known tumor antigens such as Germline-Associated Antigens (GAAs,) tumor associated antigens (TAAs) or neo antigens ( 26 – 29 ). T memory cells from bone marrow of MM were also found to kill autologous myeloma cells ( 25 ). However, common to what is found in solid tumors where neoantigen-specific T cells contribute <0.5% of CD8 T cells ( 30 ), the proportion of tumor-specific or TAA T cells in the bone marrow may also be relatively small.…”