ISSN 1866-8836
Клеточная терапия и трансплантация

BS-02. Characteristics of PD-1- and TIM-3-expressing T cells in multiple myeloma patients

Egor V. Batorov, Tatyana A. Aristova, Vera V. Denisova, Svetlana A. Sizikova, Galina Yu. Ushakova, Alexandr A. Ostanin, Elena R. Chernykh

Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia


Contact: Egor V. Batorov, phone: +7 (383) 228-21-01, e-mail: ebatorov@gmail.com

doi 10.18620/ctt-1866-8836-2023-12-3-1-176

Summary

Multiple myeloma (MM) is a B cell neoplasm with differentiation of the tumor cell clone to plasma cells. The progression of the disease in most cases remains inevitable. Previously, for MM and other hemoblastoses, an increase in counts of T cells expressing inhibitory checkpoint molecules PD-1, TIM-3, LAG-3, etc., associated with T cell dysfunction, was described. However, during clinical trials of anti-PD-1 monoclonal antibodies, both as mono- and combination therapy in patients with newly diagnosed and refractory MM, an objective response was not achieved. This work is devoted to the study of the content and functional properties of T cells expressing PD-1 and TIM-3 inhibitory checkpoint molecules in MM patients.

Materials and methods

The study included 88 patients with MM who had been treated between 2019 and 2022 at the Department of Hematology and BMT of Research Institute of Fundamental and Clinical Immunology (Novosibirsk, Russia); 60 of them underwent HDC with auto-HSCT. The counts of PD-1- and TIM-3-positive CD8+ and CD4+ T cells in the peripheral blood (PB) and bone marrow (BM) samples and intracellular expression of Ki-67, and production of granzyme B and interferon-γ were assessed by flow cytometry.

Results

Higher relative counts of PD-1+ and TIM-3+ cells were found in CD8+ and CD4+ T cells in MM patients compared with donors. In patients with MM progression, the proportions of PD-1+ and TIM-3+ T cells was increased compared to patients in remission. In both groups, the majority of studied PD-1/TIM-3-expressing cell subsets was incremented in BM samples compared to PB. CD8+PD-1+ and CD4+PD-1+ T cells in MM patients retained a pronounced cytotoxic and cytokine-producing capacity; the functional activity of TIM-3+ T cells (including those co-expressing PD-1) were significantly diminished compared to PD-1-positive subsets. After HDC with auto-HSCT, relative counts of T cells expressing PD-1 and TIM-3 were significantly increased in the first month after auto-HSCT compared with their pre-transplant counterparts. 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 significantly incremented compared to the pre-transplant levels. Six months later the frequencies and proliferative activity of PD-1/TIM-3-positive T cells were significantly reduced compared to the values at the engraftment. The proportion of CD8+PD-1+ T cells in BM samples was lower in MM patients treated with maintenance therapy with lenalidomide compared with patients treated with bortezomib. The relative counts of PD-1+ CD4+ T cells and PD-1+TIM-3+ CD8+ T cells was significantly increased in PB of patients with early relapse of MM after auto-HSCT (n=6) compared with patients who maintained remission (n=27). According to the in vitro experiments, PD-1 and TIM-3 expression increased upon stimulation of initially PD-1- and TIM-3-negative T cells with a combination of cytokines IL-2, IL-7, IL-15.

Conclusions

The counts of PD-1+, TIM-3+, PD-1+TIM-3+ subsets of T cells in MM patients were increased when compared to donors, and in patients with a disease progression compared to individuals in remission. PD-1-positive T cells in MM patients appeared to be activated or “early dysfunctional” lymphocytes, while CD8+TIM-3+ and CD4+TIM-3+ T cells, including those co-expressing PD-1, seemed to be exhausted. At early post-transplant, the proportion of T cells expressing PD-1 and TIM-3 increases due to a transient increase in their proliferative activity, probably under conditions of peripheral expansion of mature reinfused lymphocytes.

This work is supported by the Russian Science Foundation (Grant No. 20-75-10132) and within the framework №1022052600001-5-3.2.6;3.2.21.

Keywords

Multiple myeloma, PD-1, TIM-3, inhibitory checkpoint receptors, autologous hematopoietic stem cell transplantation.


Supplement 12-3
09/30/2023

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doi 10.18620/ctt-1866-8836-2023-12-3-1-176

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