CD8+ T cells exhaustion induced by myeloid-derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal-9 pathway.

Jinglian Tao,Lijuan Li,Shan Gao,Zonghong Shao,Hong Yu,Pei Liu,Dong Han,Wei Zhang,Rong Fu

doi:10.1111/jcmm.14825

Abstract

CD8+ T cells play a central role in antitumour immunity, which often exhibit ‘exhaustion’ in the setting of malignancy and chronic viral infection due to T cell immunoglobulin and mucin domain 3 (TIM3) and myeloid‐derived suppressor cells (MDSCs). Our team previously found that overactive MDSCs and exhausted TIM3+CD8+ T cells were observed in myelodysplastic syndromes (MDS) patients. However, it is not obvious whether MDSCs suppress CD8+ T cells through TIM3/Gal‐9 pathway. Here, Gal‐9, as the ligand of TIM3, was overexpressed in MDSCs. The levels of Gal‐9 in bone marrow supernatants, serum and culture supernatants of MDSCs from MDS patients were elevated. CD8+ T cells from MDS or normal controls produced less perforin and granzyme B and exhibited increased early apoptosis after co‐culture with MDSCs from MDS. Meanwhile, the cytokines produced by CD8+ T cells could be partially restored by TIM3/Gal‐9 pathway inhibitors. Furthermore, CD8+ T cells produced less perforin and granzyme B after co‐culture with excess exogenous Gal‐9, and the function of CD8+ T cells was similarly restored by TIM3/Gal‐9 pathway inhibitors. Expression of Notch1, EOMES (associated with perforin and granzyme B secretion), p‐mTOR and p‐AKT (associated with cell proliferation) was decreased in CD8+ T cells from MDS after co‐culture with excess exogenous Gal‐9. These suggested that MDSCs might be the donor of Gal‐9, and TIM3/Gal‐9 pathway might be involved in CD8+ T cells exhaustion in MDS, and that TIM3/Gal‐9 pathway inhibitor might be the promising candidate for target therapy of MDS in the future.

Highlights

Myelodysplastic syndromes (MDS) are malignant bone marrow disorders characterized by ineffective haematopoiesis and high risk to transformation into acute myeloid leukaemia
Adoptive T cell immunotherapy in neoplastic disorders has been restricted by CD8+ T cells ‘exhaustion’ due to some immune checkpoint inhibitors, such as T cell immunoglobulin and mucin domain 3 (TIM3), programmed death-1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4) and lymphocyte-activation gene 3 (LAG3).[7,8]
We explored Notch[1], eomesodermin (EOMES), phospho-mammalian target of rapamycin (mTOR) (p-mTOR) and phospho-AKT (p-AKT) proteins, which are related to the function and proliferation of CD8+ T cells,[15,16] to verify that TIM3/Gal-9 pathway might be involved in CD8+ T cells exhaustion induced by myeloid-derived suppressor cells (MDSCs) in MDS patients

Summary

| INTRODUCTION

Myelodysplastic syndromes (MDS) are malignant bone marrow disorders characterized by ineffective haematopoiesis and high risk to transformation into acute myeloid leukaemia. Increased malignant clones and cellular immunodeficiency might contribute to the pathogenesis of MDS.[1,2,3,4,5] Cytotoxic T lymphocytes (CTLs) play a central role in tumour immunity.[6] Adoptive T cell immunotherapy in neoplastic disorders has been restricted by CD8+ T cells ‘exhaustion’ due to some immune checkpoint inhibitors, such as T cell immunoglobulin and mucin domain 3 (TIM3), programmed death-1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4) and lymphocyte-activation gene 3 (LAG3).[7,8] Among these immune checkpoints, the interaction of TIM3 with its ligand galectin-9 (Gal-9) promotes Tc1 cells[9] apoptosis, CD8+T cells exhaustion,[10,11] malignant cell proliferation[12] and myeloid-derived suppressor cells (MDSCs) amplification.[13] In humans, MDSCs are usually defined as CD14−CD11b+ cells or the cells which express the myeloid marker (CD33) and are lack of lineage maturation markers and HLA-DR14 (Lin−HLA-DR−CD33+ cells). We explored Notch[1], eomesodermin (EOMES), phospho-mTOR (p-mTOR) and phospho-AKT (p-AKT) proteins, which are related to the function and proliferation of CD8+ T cells,[15,16] to verify that TIM3/Gal-9 pathway might be involved in CD8+ T cells exhaustion induced by MDSCs in MDS patients

| MATERIALS AND METHODS

Findings

| DISCUSSION