TY - JOUR

T1 - PD-1+ and TIM-3+ T cells widely express common γ-chain cytokine receptors in multiple myeloma patients, and IL-2, IL-7, IL-15 stimulation up-regulates PD-1 and TIM-3 on T cells

AU - Batorov, Egor V

AU - Ineshina, Alisa D

AU - Aristova, Tatiana A

AU - Denisova, Vera V

AU - Sizikova, Svetlana A

AU - Batorova, Daria S

AU - Ushakova, Galina Y

AU - Shevela, Ekaterina Y

AU - Chernykh, Elena R

N1 - This work is supported by the Russian Science Foundation (Grant No. 20-75-10132). © 2024 The Authors.

PY - 2024/6

Y1 - 2024/6

N2 - BACKGROUND: Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma (MM) progression. Simultaneously, previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with common γ-chain family cytokines in vitro and during homeostatic proliferation. The aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets up-regulating PD-1 and TIM-3 checkpoint molecules.METHODS: The expression of CD25, CD122, CD127 common γ-chain cytokine receptors, phosphorylated signal transducer and activator of transcription-5 (pSTAT5) and eomesodermin (EOMES) was comparatively assessed with flow cytometry in PD-1- and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM patients.RESULTS: Substantial proportions of PD-1- and TIM-3-positive T lymphocytes expressed common γ-chain cytokine receptors and pSTAT5. Frequencies of cytokine receptor expressing cells were significantly higher within TIM-3+ T cells compared to PD-1+TIM-3- subsets. Considerable proportions of both PD-1-/TIM-3-negative and positive CD8+ T cells express EOMES, while only moderate frequencies of CD4+ PD-1+/TIM-3+ T cells up-regulate this transcription factor. Besides, the surface presence of CD25 and intranuclear expression of EOMES in CD4+ T cells were mutually exclusive regardless of PD-1 and TIM-3 expression. The stimulation with common γ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+ and TIM-3+ T cell subsets in vitro.CONCLUSIONS: Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine stimulation. Differences in common γ-chain cytokine receptor expression between PD-1+ and TIM-3+ T cells may reflect functional dissimilarity of these cell subsets. Checkpoint blockade appears to alleviate lymphopenia-induced proliferation of PD-1+ T cells but may raise the possibility of immune-mediated adverse events.

AB - BACKGROUND: Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma (MM) progression. Simultaneously, previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with common γ-chain family cytokines in vitro and during homeostatic proliferation. The aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets up-regulating PD-1 and TIM-3 checkpoint molecules.METHODS: The expression of CD25, CD122, CD127 common γ-chain cytokine receptors, phosphorylated signal transducer and activator of transcription-5 (pSTAT5) and eomesodermin (EOMES) was comparatively assessed with flow cytometry in PD-1- and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM patients.RESULTS: Substantial proportions of PD-1- and TIM-3-positive T lymphocytes expressed common γ-chain cytokine receptors and pSTAT5. Frequencies of cytokine receptor expressing cells were significantly higher within TIM-3+ T cells compared to PD-1+TIM-3- subsets. Considerable proportions of both PD-1-/TIM-3-negative and positive CD8+ T cells express EOMES, while only moderate frequencies of CD4+ PD-1+/TIM-3+ T cells up-regulate this transcription factor. Besides, the surface presence of CD25 and intranuclear expression of EOMES in CD4+ T cells were mutually exclusive regardless of PD-1 and TIM-3 expression. The stimulation with common γ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+ and TIM-3+ T cell subsets in vitro.CONCLUSIONS: Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine stimulation. Differences in common γ-chain cytokine receptor expression between PD-1+ and TIM-3+ T cells may reflect functional dissimilarity of these cell subsets. Checkpoint blockade appears to alleviate lymphopenia-induced proliferation of PD-1+ T cells but may raise the possibility of immune-mediated adverse events.

KW - Humans

KW - Multiple Myeloma/immunology

KW - Hepatitis A Virus Cellular Receptor 2/metabolism

KW - Programmed Cell Death 1 Receptor/metabolism

KW - Middle Aged

KW - Male

KW - Female

KW - Aged

KW - Interleukin-7/metabolism

KW - Interleukin-15/pharmacology

KW - Up-Regulation

KW - Adult

KW - Receptors, Cytokine/metabolism

KW - T-Lymphocytes/immunology

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85204759554&origin=inward&txGid=86c4cee83ecb17e7372614f8e321dbbe

UR - https://www.mendeley.com/catalogue/abdde6c2-f58f-33d6-b28f-9106ce5ab37a/

U2 - 10.32604/or.2024.047893

DO - 10.32604/or.2024.047893

M3 - Article

C2 - 39308517

VL - 32

SP - 1575

EP - 1587

JO - Oncology research

JF - Oncology research

SN - 0965-0407

IS - 10

ER -