Pre-transplant sTIM-3 levels may have a predictive impact on transplant outcome in acute leukemia patients

Abstract

Objectives: T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) is considered as a negative regulator of T-cell driven immune response. This study is planned to investigate the prognostic role of pre-transplant soluble TIM-3 (sTIM-3) levels in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Methods: Pre-transplant serum sTIM-3 levels were measured in 177 allo-HSCT recipients [median age: 36(16-66) years; male/female: 111/66]. Results: Pre-transplant sTIM-3 levels were significantly higher in acute myeloid leukemia (AML) patients compared to acute lymphoblastic leukemia (ALL) patients (p = 0.01). Pre-transplant sTIM-3 levels were significantly lower in patients with abnormal cytogenetics (p = 0.017). Pre-transplant sTIM-3 levels were significantly higher in patients who developed viral hemorrhagic cystitis (p = 0.034). A positive correlation was demonstrated between sTIM-3 levels and acute graft versus host disease (GvHD) grade (p = 0.013; r = 0.299). Overall survival (OS) was not statistically different between low-and high-TIM-3 groups (% 35.2 vs %20.4; p > 0.05). Primary diagnosis (p = 0.042), sinusoidal obstruction syndrome (p < 0.001), acute GvHD (p = 0.001), chronic GvHD (p = 0.009) and post-transplant relapse (p = 0.003) represented significant impact on OS. Discussion: Increased sTIM-3 levels in AML patients seem to be compatible with the previous reports. The inhibitor role of TIM-3 in cellular immune response may be a possible explanation for the association of sTIM-3 with viral infections and GvHD. However, the main challenge remains to be the ambiguous association of pre-transplant sTIM-3 levels and post-transplant complications, as allo-HSCT recipients are expected to represent donor genetic features in the post-transplant setting. Conclusion: Further studies are warranted to clarify the particular role of sTIM-3 in the allo-HSCT setting.

Soluble T Cell Immunoglobulin and Mucin Domain-3 (sTIM-3) Predicts Graft-Versus-Host Disease (GVHD) in Iranian Allogeneic Hematopoietic Stem Cell Transplantation

“…Our results showed that the plasma level of sTIM-3 in grade 2 -4 aGVHD was higher compared to grade 1 aGVHD and control group. Our results are in agreement with previous studies that reported that the sTIM-3 plasma level in aGVHD was increased, and this could be a predictive biomarker of GVHD in allo-HSCT patients (8,37). Understanding the TIM-3-mediated immune regulation can provide insight for new approaches to enhance the prevention of the alloimmune response.…”

“…Therefore, it has been suggested that increased plasma levels of sTIM-3 may have roles in the pathogenesis by inhibiting the binding of TIM-3 to its ligand and interfering with the regulatory activity of TIM-3 molecules on the surface of T cells (31). The sTIM-3 in the plasma could be passively released from apoptotic cells of GVHD patients (8,37). In our study, the higher plasma levels of sTIM-3 in severe GVHD patients confirm the association of sTIM-3 with aGVHD.…”

Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy

“…Most studies indicated that overexpression of TIM-3 either on immune cells or tumor cells is associated with poor OS for patients, such as patients with GC [88], and high-risk groups, showing poor prognosis, and lower complete response (CR) rates following induction chemotherapy in patients with AML as well as highrisk patients with B cell acute lymphoblastic lymphoma (B-ALL) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) [97][98][99][100]. Moreover, a Phase I trial (NCT02573363) demonstrated that higher TIM-3/Gal-9 expression was associated with chemotherapy resistance in patients with AML [101].…”

Changes in serum TIM-3 and complement C3 expression in workers due to Mn exposure

“…At present, domestic and international studies on Mn and immune checkpoints are mainly focused on the field of Mn 2+ as an interferon gene-stimulating factor agonist combined with immune checkpoint inhibitors for antitumor therapy (24), but no studies on immune checkpoints as markers of Mn exposure effects have been found. Considerably, several studies have demonstrated that high concentrations of TIM-3 can be detected in plasma or serum of cancers such as lung, gastric, liver, and cervical cancers and systemic inflammatory patients such as those with chronic hepatitis B virus infection and transplantation of patients with acute leukemia (25), suggesting that it may be associated with a poor prognosis of the disease, affirming its value as a prognostic or predictive marker for predicting the disease or assessing the response to immunotherapy. In this study, after controlling for smoking, alcohol consumption and obesity influencing factors, the dose-response relationship between Mn internal exposure dose and TIM-3 was analyzed and it was found that the concentration of TIM-3 in the serum of the workers tended to increase with the increase of the internal exposure dose, which indicated that the measured circulating level of TIM-3 may be correlated with the dose of the toxic exposure, suggesting that TIM-3 has a potential value as a marker of the effect of Mn exposure.…”