Natural killer cells and bone marrow mesenchymal stem cells: A dangerous liaison in multiple myeloma

Accounting for 10% of all blood cancers, multiple myeloma (MM) is an incurable haematological malignancy characterized by the accumulation of clonal plasma cells in the bone marrow (BM) of patients. This malignancy often develops in elderly patients through the accumulation of a heterogeneous range of cytogenetic abnormalities that promote tumour growth and survival in the BM microenvironment.1

The gold standard for the treatment of newly diagnosed patients without co-morbidities remains high-dose chemotherapy plus autologous stem cell transplantation. Unfortunately, MM patients relapse after each treatment regimen, leading to a continuous and dynamic search for new non-refractory therapeutic options.2 Novel agents including immunomodulatory drugs, proteasome inhibitors, dexamethasone and more recently monoclonal antibodies have transformed the treatment paradigm of MM. Nowadays, these agents are extensively used in the clinic to target relapsed and refractory diseases. Of particular interest, immune checkpoint inhibitors have emerged as powerful tools to disrupt the deeply immunosuppressive interactions in the BM MM microenvironment, considered the main obstacle to tackle in the fight against MM.3

Natural killer (NK) cells are a unique lymphocyte population able to exert cytotoxic activity without prior sensitization, highlighting their importance in innate anti-tumour immunity. MM cells are known to express low levels of major histocompatibility class I on their surface, rendering them vulnerable to NK cell recognition and attack and subsequently highlighting the potential of NK surveillance in MM control.4 Nevertheless, NK cells fail to acquire a functional cytotoxic phenotype amidst the highly immunosuppressive BM MM immune landscape and become increasingly exhausted as the disease develops.

In a recent letter, Liu, Deng et al.5 introduce T cell immunoglobulin and immunoreceptor tyrosine (TIGIT)-based inhibitory motif domain) as a promising target to counteract BM-mesenchymal stem cells (MSC)-mediated NK cell exhaustion and restore NK cell anti-tumour activity in MM (Figure 1). TIGIT is a co-inhibitory receptor expressed on both T cells and NK cells, where it plays a key immunomodulatory role by inhibiting their effector function through binding its cognate ligand CD155. The immunoglobulin domain of TIGIT resembles that of the activation receptor CD226, also expressed by NK cells and both receptors can bind the same subset of ligands CD155, CD112 and CD113.6 Supporting their hypothesis, Zhao-Yun et al., confirm the elevated expression of TIGIT in NK cells at different stages of MM, along with a decrease in activation receptors (NKG2D and CD107a) and functional biomarkers (interferon [IFN]-γ and perforin). Interestingly, the expression of CD226 was reduced at the early stages of the disease.