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



Cite item

Full Text

Abstract

Abstract

Multiple myeloma (MM) is an incurable disease that often recurrens after treatment, including high-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (auto-HSCT). One of the circumstances to achieving long-term remission is the tumor microenvironment, the immunosuppressive effects of which are realized due to non-classical HLA class Ib molecules—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 research a comparative analysis of the expression of HLA-G/E/DR molecules and countof among of main populations of immunocompetent cells (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 volunteers. The results showed that after therapy, the patients had a significant decrease of the total CD3+ T-lymphocyte, including CD8+ and CD4+HLA-G+ subpopulations (p<0.05), reflecting the cumulative immunosuppressive effect of the melphalan-based conditioning regimen. A decrease in the 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 paradoxical increase in the proportion of CD8+ T-lymphocytes against the background of general lymphopenia is probably associated with clonal expansion of antigen-specific populations with the phenotype of "exhausted" T-cells, which requires further study.

The results obtained emphasize the dualistic role of HLA molecules in the pathogenesis of MM: HLA-E/G act as key mediators of immunosuppression, while HLA-DR potentiates the antitumor response. The discovered imbalance opens up new prospects for further study of the role of HLA molecules in the tumor process, which can be used for personalized therapy, including targeted blockade of NKG2A/LILRB1 receptors or HLA Ib molecules and the development of prognostic models based on a comprehensive analysis of HLA-G/E/DR expression.

About the authors

Ivan Pavlovich Skachkov

Federal State Budgetary Scientific Institution, “Research Institute of Fundamental and Clinical Immunology” (RIFCI), Novosibirsk, Russia;
Novosibirsk State Medical University, Novosibirsk, Russia

Email: pavania02@gmail.com
ORCID iD: 0009-0000-0530-3818

laboratory research assistant, 6th year student of the Faculty of Medicine

Russian Federation, Russia, 630099, Novosibirsk, Yadrintsevskaya St., 14; Russia, 630091, Siberian Federal District, Novosibirsk Region, Novosibirsk, Krasny Prospekt, 52

Alina Alexandrovna Aktanova

Federal State Budgetary Scientific Institution, “Research Institute of Fundamental and Clinical Immunology” (RIFCI), Novosibirsk, Russia;
Novosibirsk State Medical University, Novosibirsk, Russia

Email: aktanova_al@mail.ru
ORCID iD: 0000-0002-2075-8551
SPIN-code: 2419-7412

Junior Researcher of laboratory of clinical immunopathology of RIFCI, assistant of department of clinical immunology, Faculty of Medicine, NSMU

Russian Federation, Russia, 630099, Novosibirsk, Yadrintsevskaya St., 14; Russia, 630091, Siberian Federal District, Novosibirsk Region, Novosibirsk, Krasny Prospekt, 52

Vera Vasilievna Denisova

Clinic of Immunopathology (CI) of RIFCI, Novosibirsk, Russia

Email: verden@bk.ru
ORCID iD: 0000-0003-1951-2260
SPIN-code: 5507-1870
Scopus Author ID: 54881246800

Candidate of Medical Sciences, Head of the Hematology Department with a Bone Marrow Transplant Unit, Hematologist of the Highest Category

Russian Federation, Russia, 630047, Novosibirsk, Zalesskogo st., 6 k9

Ekaterina Aleksandrovna Pashkina

Federal State Budgetary Scientific Institution, “Research Institute of Fundamental and Clinical Immunology” (RIFCI), Novosibirsk, Russia;
Novosibirsk State Medical University, Novosibirsk, Russia

Author for correspondence.
Email: pashkina.e.a@yandex.ru
ORCID iD: 0000-0002-4912-5512
SPIN-code: 2279-9539
Scopus Author ID: 54788235800
ResearcherId: N-7398-2016

PhD, Head of the Laboratory of Immune Response Regulation, Senior Researcher at the Laboratory of Clinical Immunopathology at the RIFCI, Associate Professor at the Department of Clinical Immunology at the Novosibirsk State Medical University

Russian Federation, Russia, 630099, Novosibirsk, Yadrintsevskaya St., 14; Russia, 630091, Siberian Federal District, Novosibirsk Region, Novosibirsk, Krasny Prospekt, 52

References

  1. Баторов Е. В., Сергеевичева В. В., Аристова Т. А., Сизикова С. А., Ушакова Г. Ю., Гилевич А. В., Шевела Е. Я., Останин А. А., Черных Е. Р. Экспрессия ингибиторных сигнальных молекул PD-1 И TIM-3 Т-лимфоцитами в раннем посттрансплантационном периоде у больных множественной миеломой // Гематология и трансфузиология. – 2021. – №4. – С. 499-511.
  2. Batorov E.V., Sergeevicheva V.V., Aristova T.A., Sizikova S.A., Ushakova G.Y., Gilevich A.V., Shevela E.A., Ostanin A.A., Chernykh E.R. Expression of PD-1 and TIM-3 inhibitory checkpoint molecules by T-lymphocytes in early post-transplant period in multiple myeloma patients. Russian Journal of Hematology and Transfusiology (Gematologiya i transfuziologiya). 2021, Vol. 66, no. 4, pp. 499–511. http://elib.fesmu.ru/Article.aspx?id=420894
  3. [https://doi.org/10.35754/0234-5730-2021-66-4-499-511]
  4. Accolla R.S., Ramia E., Tedeschi A., Forlani G. CIITA-driven MHC class II expressing tumor cells as antigen presenting cell performers: toward the construction of an optimal anti-tumor vaccine. Front. Immunol. 2019, Vol. 10, 1806. - https://pubmed.ncbi.nlm.nih.gov/31417570/
  5. [doi: 10.3389/fimmu.2019.01806]
  6. Brown R., Kabani K., Favaloro J., Yang S., Ho P.J., Gibson J., Fromm P., Suen H., Woodland N., Nassif N., Hart D., Joshua D. CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis. Blood. 2012, Vol. 120, no. 10, pp. 2055-2063. - https://pubmed.ncbi.nlm.nih.gov/22705596/
  7. [doi: 10.1182/blood-2012-03-416792]
  8. Brown Ross D., Kabani K., Yang S., Aklilu E., Joy P., Gibson J., Joshua D. E. HLA-G and CD86 Expression on Malignant Plasma Cells Convey a Poor Prognosis and Immunoregulate T Cells In Patients with Myeloma. J. Blood, 2010, Vol. 116, no. 21, 983. - https://pubmed.ncbi.nlm.nih.gov/19883313/
  9. [doi: 10.1182/blood.V116.21.983.983]
  10. Cardona-Benavides I.J., de Ramón C., Gutiérrez N.C. Genetic Abnormalities in Multiple Myeloma: Prognostic and Therapeutic Implications. Cells. 2021, Vol. 10, no. 2, 336. - https://pubmed.ncbi.nlm.nih.gov/33562668/
  11. [doi: 10.3390/cells10020336]
  12. de Kruijf E.M., Sajet A., van Nes J.G., Natanov R., Putter H., Smit V.T., Liefers G.J., van den Elsen P.J., van de Velde C.J., Kuppen P.J. HLA-E and HLA-G expression in classical HLA class I-negative tumors is of prognostic value for clinical outcome of early breast cancer patients. J Immunol. 2010, Vol. 185, no. 12, pp. 7452-7459. - https://pubmed.ncbi.nlm.nih.gov/21057081/
  13. [doi: 10.4049/jimmunol.1002629]
  14. Garziera M., Scarabel L., Toffoli G. Hypoxic Modulation of HLA-G Expression through the Metabolic Sensor HIF-1 in Human Cancer Cells., J. Immunol Res. 2017, 2017. - https://pubmed.ncbi.nlm.nih.gov/28781970/
  15. [doi: 10.1155/2017/4587520]
  16. Heng Y., Zhu X., Wu Q., Lin H., Ding X., Tao L., Lu L. High Expression of Tumor HLA-DR Predicts Better Prognosis and Response to Anti-PD-1 Therapy in Laryngeal Squamous Cell Carcinoma. Transl Oncol. 2023, Vol. 33. - https://pubmed.ncbi.nlm.nih.gov/37149969/
  17. [doi: 10.1016/j.tranon.2023.101678]
  18. Kaiser B.K., Pizarro J.C., Kerns J., Strong R.K. Structural basis for NKG2A/CD94 recognition of HLA-E. Proc Natl Acad Sci U.S.A., 2008, Vol. 105, no. 18, pp. 6696-6701. - https://pubmed.ncbi.nlm.nih.gov/18448674/
  19. [doi: 10.1073/pnas.0802736105]
  20. Le Maoult J., Rouas-Freiss N., Le Discorde M., Moreau P., Carosella E.D. HLA-G en transplantation d'organes [HLA-G in organ transplantation]. Pathol Biol (Paris), 2004, Vol. 52, no. 2, pp. 97-103. French. - https://pubmed.ncbi.nlm.nih.gov/15001239/
  21. [doi: 10.1016/j.patbio.2003.04.006]
  22. Lv J., Sun H., Gong L., Wei X., He Y., Yu Z., Liu L., Yi S., Sui W., Xu Y., Deng S., An G., Yao Z., Qiu L., Hao M. Aberrant metabolic processes promote the immunosuppressive microenvironment in multiple myeloma. Front Immunol. 2022, Vol. 13. - https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1077768/full
  23. [doi: 10.3389/fimmu.2022.1077768]
  24. Mendonça de Pontes R., Flores-Montero J., Sanoja-Flores L., Puig N., Pessoa de Magalhães R.J., Corral-Mateos A., Salgado A.B., García-Sánchez O., Pérez-Morán J., Mateos M.V., Burgos L., Paiva B., Te Marvelde J., van der Velden V.H.J, Aguilar C., Bárez A., García-Mateo A., Labrador J., Leoz P., Aguilera-Sanz C., Durie B., van Dongen J.J.M., Maiolino A., Sobral da Costa E., Orfao A. B-Cell Regeneration Profile and Minimal Residual Disease Status in Bone Marrow of Treated Multiple Myeloma Patients. Cancers (Basel). 2021, Vol. 13, no. 7, 1704. - https://www.researchgate.net/publication/350619241_B-Cell_Regeneration_Profile_and_Minimal_Residual_Disease_Status_in_Bone_Marrow_of_Treated_Multiple_Myeloma_Patients
  25. [doi: 10.3390/cancers13071704]
  26. Ozga M., Zhao Q., Huric L., Miller C., Rosko A., Khan A., Umyarova E., Benson D., Cottini F. Concomitant 1q+ and t(4;14) influences disease characteristics, immune system, and prognosis in double-hit multiple myeloma. Blood Cancer J. 2023, Vol.13, no. 1, 167. - https://pubmed.ncbi.nlm.nih.gov/37949844/
  27. [doi: 10.1038/s41408-023-00943-2]
  28. Pankratz S., Bittner S., Herrmann A.M., Schuhmann M.K., Ruck T., Meuth S.G., Wiendl H. Human CD4+ HLA-G+ regulatory T cells are potent suppressors of graft-versus-host disease in vivo. FASEB J. 2014, Vol. 28, no. 8, pp. 435-445. - https://pubmed.ncbi.nlm.nih.gov/24744146/
  29. [doi: 10.1096/fj.14-251074]
  30. Żyłka K., Kubicki T., Gil L., Dytfeld D. T-cell exhaustion in multiple myeloma. Expert Rev Hematol. 2024, Vol, 17, no. 7, pp. 295-312. - https://pubmed.ncbi.nlm.nih.gov/38919090/
  31. [doi: 10.1080/17474086.2024.2370552]

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) Skachkov I., Aktanova A., Denisova V., Pashkina E.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № 77 - 11525 от 04.01.2002.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies