Open Access

ARTICLE

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

by EGOR V. BATOROV^1,2,*, ALISA D. INESHINA², TATIANA A. ARISTOVA³, VERA V. DENISOVA³, SVETLANA A. SIZIKOVA³, DARIA S. BATOROVA³, GALINA Y. USHAKOVA³, EKATERINA Y. SHEVELA¹, ELENA R. CHERNYKH¹

1 Laboratory of Cellular Immunotherapy, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia
2 V. Zelman Institute of Medicine and Psychology, Novosibirsk National Research State University, Novosibirsk, 630090, Russia
3 Department of Hematology and Bone Marrow Transplantation, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia

* Corresponding Author: EGOR V. BATOROV. Email:

Oncology Research 2024, 32(10), 1575-1587. https://doi.org/10.32604/or.2024.047893

Received 21 November 2023; Accepted 09 April 2024; Issue published 18 September 2024

Abstract

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.

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