Explore the vast range of titles available.

T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) expression has been a trending topic in recent years due to its differential expression in a wide range of neoplasms. TIM-3 is one of the key immune checkpoint receptors that interact with GAL-9, PtdSer, HMGB1 and CEACAM1. Initially identified on the surface of T helper 1 (Th1) lymphocytes and later on cytotoxic lymphocytes (CTLs), monocytes, macrophages, natural killer cells (NKs), and dendritic cells (DCs), TIM-3 plays a key role in immunoregulation. Recently, a growing body of evidence has shown that its differential expression in various tumor types indicates a specific prognosis for cancer patients. Here, we discuss which types of cancer TIM-3 can serve as a prognostic factor and the influence of coexpressed immune checkpoint inhibitors, such as LAG-3, PD-1, and CTLA-4 on patients' outcomes. Currently, experimental medicine involving TIM-3 has significantly enhanced the anti-tumor effect and improved patient survival. In this work, we summarized clinical trials incorporating TIM-3 targeting monoclonal and bispecific antibodies in monotherapy and combination therapy and highlighted the emerging role of cell-based therapies.

In one decade, immunotherapy based on immune checkpoint blockades (ICBs) has become a new pillar of cancer treatment following surgery, radiation, chemotherapy, and targeted therapies. However, not all cancer patients benefit from single or combination therapy with anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies. Thus, an increasing number of immune checkpoint proteins (ICPs) have been screened and their effectiveness evaluated in preclinical and clinical trials. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) constitute the second wave of immunotherapy targets that show great promise for use in the treatment of solid tumors and leukemia. To promote the research and clinical application of ICBs directed at these targets, we summarize their discovery, immunotherapy mechanism, preclinical efficiency, and clinical trial results in this review.

The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

Immunosuppression is increasingly being recognized as one of the causes of increased morbidity and mortality during sepsis. Both innate and adaptive immune system dysfunction have been shown to cause an impaired ability to eradicate the primary infection and also lead to frequent occurrence of secondary opportunistic infections. Pre-clinical and clinical studies have shown that inhibitory immune checkpoint molecules, including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell membrane protein-3 (TIM-3), Lymphocyte activation-gene-3 (LAG-3) and 2B4, are upregulated during the course of sepsis. Engagement of these inhibitory molecules on various immune cells has been consistently shown to inhibit innate immune cell functions (e.g., phagocytosis, cytokine production and pathogen clearance) and also lead to impaired T cell competence. In numerous pre-clinical models of sepsis, therapeutic agents aimed at blocking engagement of inhibitory immune checkpoints on immune cells have been shown to improve innate and adaptive immune cell functions, increase host resistance to infection and significantly improve survival. Therefore, immunotherapy with immune cell checkpoint inhibitors holds significant potential for the future of sepsis therapy and merits further investigation.

Macrophages are a subset of mononuclear phagocytes of the innate immune system with high plasticity and heterogeneity. At the maternal-fetal interface, macrophages are present in all stages of pregnancy and involved in a variety of activities, including regulation of immune cell activities, decidualization, placental cell invasion, angiogenesis, parturition, and postpartum uterine involution. The activation state and function of uterine-placental macrophages are largely dependent on the local tissue microenvironment. However, disruption of the uterine microenvironment can have profound effects on macrophage activity and subsequently impact pregnancy outcome. Thus, appropriately and timely regulated macrophage polarization has been considered a key determinant of successful pregnancy. Targeting macrophage polarization might be an efficient strategy for maintaining maternal-fetal immune homeostasis and a normal pregnancy. Here, we will review the latest findings regarding the modulators regulating macrophage polarization in healthy pregnancies and pregnancy complications, which might provide a basis for macrophage-centered therapeutic strategies.

Human cancer cells operate a variety of effective molecular and signaling mechanisms which allow them to escape host immune surveillance and thus progress the disease. We have recently reported that the immune receptor Tim-3 and its natural ligand galectin-9 are involved in the immune escape of human acute myeloid leukemia (AML) cells. These cells use the neuronal receptor latrophilin 1 (LPHN1) and its ligand fibronectin leucine rich transmembrane protein 3 (FLRT3, and possibly other ligands) to trigger the pathway. We hypothesized that the Tim-3-galectin-9 pathway may be involved in the immune escape of cancer cells of different origins. We found that studied breast tumors expressed significantly higher levels of both galectin-9 and Tim-3 compared to healthy breast tissues of the same patients and that these proteins were co-localized. Increased levels of LPHN2 and expressions of LPHN3 as well as FLRT3 were also detected in breast tumor cells. Activation of this pathway facilitated the translocation of galectin-9 onto the tumor cell surface, however no secretion of galectin-9 by tumor cells was observed. Surface-based galectin-9 was able to protect breast carcinoma cells against cytotoxic T cell-induced death. Furthermore, we found that cell lines from brain, colorectal, kidney, blood/mast cell, liver, prostate, lung, and skin cancers expressed detectable amounts of both Tim-3 and galectin-9 proteins. The majority of cell lines expressed one of the LPHN isoforms and FLRT3. We conclude that the Tim-3-galectin-9 pathway is operated by a wide range of human cancer cells and is possibly involved in prevention of anti-tumor immunity.

Cancer immunotherapy has produced impressive clinical results in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), a large portion of cancer patients have not yet benefited from this novel therapy. T cell immunoglobulin and mucin domain 3 (TIM-3) has been shown to mediate immune tolerance in mouse models of infectious diseases, alloimmunity, autoimmunity, and tumor Immunity. Thus, targeting TIM-3 emerges as a promising approach for further improvement of current immunotherapy. Despite a large amount of experimental data showing an immune suppressive function of TIM-3 in vivo, the exact mechanisms are not well understood. To enable effective targeting of TIM-3 for tumor immunotherapy, further in-depth mechanistic studies are warranted. These studies will also provide much-needed insight for the rational design of novel combination therapy with other checkpoint blockers. In this review, we summarize key evidence supporting an immune regulatory role of TIM-3 and discuss possible mechanisms of action.

Acute Myeloid Leukemia (AML) remains a therapeutic challenge due to immune evasion and relapse. T-cell immunoglobulin and mucin domain-containing-3 (TIM-3) is an immune checkpoint receptor aberrantly expressed on immune cells and leukemic stem cells (LSCs) in AML. Biologically, TIM-3 predominantly mediates deleterious effects, promoting T-cell/NK dysfunction and supporting LSC self-renewal, but this pathogenic expression also makes TIM-3 a therapeutically actionable target. This narrative review synthesizes current preclinical and clinical evidence on the role of TIM-3 in AML. We examined its structure, signaling pathways, and dual functions in promoting immune suppression and LSC self-renewal. A comprehensive analysis of ongoing therapeutic strategies, including monoclonal antibodies and cellular therapies, was conducted. Relevant literature was identified through searches of PubMed, Scopus, and Web of Science databases, with a focus on recently published studies. TIM-3 contributes to immune dysregulation by inducing T-cell exhaustion, impairing NK cell cytotoxicity, and enhancing immunosuppressive myeloid cells. Concurrently, its expression on LSCs drives leukemogenesis through autocrine signaling loops involving Galectin-9 and the β-catenin pathway. Preclinical studies show that TIM-3 blockade reduces leukemic stem-cell frequency and impairs LSC reconstitution in xenograft models, and can reinvigorate anti-leukemic immunity in experimental systems; however, these findings are preclinical and have not yet translated into consistent, randomized clinical benefit in human trials, underscoring the need for biomarker-guided and combination approaches in clinical development (Kikushige et al. Cell Stem Cell 17(3):341–352, 2015; Kikushige et al. Cell Stem Cell7(6):708–717, 2010; Zeidan et al. Lancet Haematol11(1):e38–e50, 2024). Clinically, the anti-TIM-3 antibody sabatolimab showed a tolerable safety profile and preliminary signals of activity when combined with hypomethylating agents; however, randomized phase II data did not demonstrate statistically significant improvements in the primary endpoints (complete response rate and progression-free survival), and the development program has since been re-evaluated in light of these results. TIM-3 also shows promise as a diagnostic and prognostic biomarker. TIM-3 plays an important and multifaceted role in AML pathogenesis, with evidence supporting both immune-regulatory functions and roles in leukemic stem cell biology; however, definitive proof that TIM-3 is essential for LSC maintenance across all AML subtypes requires additional genetic and functional validation. Targeting TIM-3 remains a biologically compelling strategy to address immune suppression and LSC biology in AML, but definitive clinical benefit has not been established in randomized studies to date; further investigation, especially in biomarker-enriched, low-tumor-burden settings and rational combinations, is required to define its clinical role.

The relationship between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host immunity is poorly understood. We performed an extensive analysis of immune responses in 32 patients with severe COVID-19, some of whom succumbed. A control population of healthy subjects was included. Patients with COVID-19 had an altered distribution of peripheral blood lymphocytes, with an increased proportion of mature natural killer (NK) cells and low T-cell numbers. NK cells and CD8+ T cells overexpressed T-cell immunoglobulin and mucin domain-3 (TIM-3) and CD69. NK cell exhaustion was attested by increased frequencies of programmed cell death protein 1 (PD-1) positive cells and reduced frequencies of natural killer group 2 member D (NKG2D)-, DNAX accessory molecule-1 (DNAM-1)- and sialic acid-binding Ig-like lectin 7 (Siglec-7)-expressing NK cells, associated with a reduced ability to secrete interferon (IFN)γ. Patients with poor outcome showed a contraction of immature CD56bright and an expansion of mature CD57+ FcεRIγneg adaptive NK cells compared to survivors. Increased serum levels of IL-6 were also more frequently identified in deceased patients compared to survivors. Of note, monocytes secreted abundant quantities of IL-6, IL-8, and IL-1β which persisted at lower levels several weeks after recovery with concomitant normalization of CD69, PD-1 and TIM-3 expression and restoration of CD8+ T cell numbers. A hyperactivated/exhausted immune response dominate in severe SARS-CoV-2 infection, probably driven by an uncontrolled secretion of inflammatory cytokines by monocytes. These findings unveil a unique immunological profile in COVID-19 patients that will help to design effective stage-specific treatments for this potentially deadly disease.

Abstract Context Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in medullary thyroid carcinoma (MTC). Objective We aimed to provide the first evidence regarding the expression profiles and clinical significance of CIRs in a large cohort of MTC patients. Design and Patients In total, 200 MTC patients who received initial surgery in our hospital were included. Immunohistochemistry was performed to evaluate CIR expressions in tissue microarrays (TMAs). Combined with the results of our previous programmed cell death ligand-1 (PD-L1) study, clinicopathologic and prognostic correlations of these proteins were retrospectively analyzed. Results TIM-3, PD-1, CTLA-4, LAG-3, and TIGIT positivity was detected in 96 (48.0%), 27 (13.5%), 25 (12.5%), 6 (3.0%), and 6 (3.0%) patients, respectively, in whom TIM-3, PD-1, and CTLA-4 expressions were positively correlated. Log-rank tests and multivariate Cox analyses both indicated that TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression were associated with worse structural recurrence-free survival. In addition, among 20 patients who developed advanced disease during follow-up, 12 (60%) showed TIM-3 positivity, among whom 6 cases also had concurrent moderate to strong PD-1, PD-L1, or CTLA-4 expression. Conclusions Using the currently largest TMA cohort of this rare cancer, we delineated the CIR expression profiles in MTC, and identified TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced MTCs are probably immunogenic, for which single or combined immunotherapy including TIM-3, PD-1, PD-L1, or CTLA-4 blockade may be potential therapeutic approaches in the future.