Immune status and expression of HLA-E, HLA-G and HLA-DR molecules on conventional T lymphocytes in patients with multiple myeloma before and after autologous hematopoietic stem cell transplantation

Multiple myeloma (MM) is an incurable disease with common recurrence after treatment, including high-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (auto-HSCT). Tumor microenvironment is a factor of achieving long-term remission. Its immunosuppressive effects are mediated due to non-classical HLA class Ib molecules, i.e., HLA-E and HLA-G. These molecules interact with inhibitory receptors (NKG2A/CD94 for HLA-E; ILT2, ILT4, KIR2DL4 for HLA-G) on the surface of NK and T lymphocytes, blocking their cytotoxic activity and facilitating tumor evasion from immune surveillance. In contrast, the classical HLA-DR molecule plays an opposite role, enhancing antitumor immunity through the activation of CD4⁺T helpers. In this study, a comparative analysis of HLA-G/E/DR expression and counts of main immunocompetent cell populations (CD4⁺, CD8⁺, NK, NKT cells, B lymphocytes, monocytes) were performed by flow cytometry method in 10 patients with MM before and after HDC with auto-HSCT, and in 8 healthy volunteers. The results showed that, after therapy, the patients had a significant decrease of total CD3⁺T lymphocyte counts, including CD8⁺ and CD4⁺HLA-G⁺ subpopulations (p < 0.05), thus reflecting a cumulative immunosuppressive effect of melphalan-based conditioning. A decreased number of CD4⁺HLA-G⁺ cells, which have regulatory properties and are capable of suppressing the immune response, may indicate partial destruction of the tumor niche. At the same time, a paradoxically increased proportion of CD8⁺T lymphocytes, along with general lymphopenia, may be associated with clonal expansion of antigen-specific populations with “exhausted” T cell phenotype which requires further study. The results obtained suggest a dualistic role of HLA molecules in pathogenesis of MM: HLA-E/G act as key mediators of immunosuppression, while HLA-DR potentiates antitumor response. The discovered imbalance opens up new prospects for further studies of a role of HLA molecules in the tumor process, which may be applied to personalized therapy, including targeted blockade of NKG2A/LILRB1 receptors or HLA Ib molecules, and development of prognostic models based on a comprehensive analysis of HLA-G/E/DR expression.