Expression of PD-1 and TIM-3 inhibitory checkpoint molecules by T-lymphocytes in early post-transplant period in multiple myeloma patients
https://doi.org/10.35754/0234-5730-2021-66-4-499-511
Abstract
Introduction. High-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of treatment for multiple myeloma (MM) patients. The post-transplant period appears to be promising for targeted anti-checkpoint therapy in MM.
Aim — to study the dynamics and functional properties of T-cells expressing inhibitory checkpoint molecules PD-1 and TIM-3 in patients with MM under conditions of lymphopenia after HDC with auto-HSCT.
Methods. The study included 40 patients with MM who underwent HDC with auto-HSCT. The counts of PD-1- and TIM3-positive CD8+ and CD4+ T-cells and their functional activity on the intracellular expression of Ki-67, production of granzyme B, and interferon-γ were assessed by fl ow cytometry.
Results. Relative counts of patient PD-1+ and TIM-3+ subsets of CD8+ and CD4+ T-cells obtained from bone marrow samples were higher compared to peripheral blood. CD8+ PD-1+ and CD4+ PD-1+ T-cells of MM patients had a pronounced cytotoxic and cytokine-producing potential. The functional activity of CD8+ TIM-3+ and CD4+ TIM-3+ T-cells was signifi cantly reduced compared with TIM-3-negative subsets. Low functional activity was also detected in populations of CD8+ and CD4+ T-lympho cytes, co-expressing PD-1 and TIM-3. The frequencies of T-cells expressing PD-1 and TIM-3 increased signifi cantly on the engraftment day after auto-HSCT. The proliferative activity of PD-1+ and TIM-3+ CD4+ and CD8+ T-cells and the cytotoxic potential of PD-1+ and TIM-3+ CD8+ T-cells were also signifi cantly increased compared to the data prior auto-HSCT.
Conclusions. PD-1-positive T-cells in MM patients are related to activated or “early dysfunctional” but not exhausted subsets, while T-cells exhaustion is more analogous with CD8+ TIM-3+ and CD4+ TIM-3+ T-cells, as well as with subsets co-expressing PD-1 and TIM-3. To identify the state of T-cells exhaustion, it is necessary to evaluate T-cells subsets co-expressing PD-1, TIM-3, and other ICMs, and/or to study their functional properties. In the early post-transplant period, the proportion of Tcells expressing PD-1 and TIM-3 increases due to an increase in their proliferative potential.
Keywords
About the Authors
E. V. BatorovRussian Federation
Egor V. Batorov, Cand. Sci. (Med.), Senior Researcher, Laboratory of Cellular Immunotherapy
630099, Novosibirsk
V. V. Sergeevicheva
Russian Federation
Vera V. Sergeevicheva, Cand. Sci. (Med.), Head of the Department of Haematology with Bone Marrow Transplantation Unit
630099, Novosibirsk
T. A. Aristova
Russian Federation
Tatiana A. Aristova, Physician, Department of Haematology with Bone Marrow Transplantation Unit
630099, Novosibirsk
S. A. Sizikova
Russian Federation
Svetlana A. Sizikova, Cand. Sci. (Med.), Physician, Department of Haematology with Bone Marrow Transplantation Unit
630099, Novosibirsk
G. Y. Ushakova
Russian Federation
Galina Yu. Ushakova, Cand. Sci. (Med.), Physician, Department of Haematology with Bone Marrow Transplantation Unit
630099, Novosibirsk
A. V. Gilevich
Russian Federation
Andrey V. Gilevich, Cand. Sci. (Med.), Head of the Intensive Care Unit
630099, Novosibirsk
E. A. Shevela
Russian Federation
Ekaterina Ya. Shevela, Dr. Sci. (Med.), Leading Researcher, Laboratory of Cellular Immunotherapy
630099, Novosibirsk
A. A. Ostanin
Russian Federation
Alexander A. Ostanin, Dr. Sci. (Med.), Professor, Chief Researcher, Laboratory of Cellular Immunotherapy
630099, Novosibirsk
E. R. Chernykh
Russian Federation
Elena R. Chernykh, Dr. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Cellular Immunotherapy
630099, Novosibirsk
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Review
For citations:
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. 2021;66(4):499-511. (In Russ.) https://doi.org/10.35754/0234-5730-2021-66-4-499-511