Lymphocyte Activation Gene-3 Research Articles

Precision Oncology in Melanoma: Changing Practices.

Over the last 2 decades, significant progress has been made in our understanding of the genomics, tumor immune microenvironment, and immunogenicity of malignant melanoma. Historically, the prognosis for metastatic melanoma was poor because of limited treatment options. However, after multiple landmark clinical trials displaying the efficacy of combined BRAF/MEK inhibition for BRAF-mutant melanoma and the application of immune checkpoint inhibitors targeting the programmed death-1, cytotoxic T-lymphocyte antigen-4, and lymphocyte activation gene-3 molecules, overall survival rates have dramatically improved. The role of immune checkpoint inhibition has since expanded to the neoadjuvant and adjuvant settings with multiple regimens in routine use. Personalized therapies, including tumor-infiltrating lymphocytes that are extracted from a patient's melanoma and eventually reinfused into the patient, and messenger RNA vaccines used to target neoantigens unique to a patient's tumor, show promise. Improvements in accompanying imaging modalities, particularly within the field of nuclear medicine, have allowed for more accurate staging of disease and assessment of treatment response. Continued growth in the role of nuclear medicine in the evaluation of melanoma, including the incorporation of artificial intelligence into image interpretation and use of radiolabeled tracers allowing for intricate imaging of the tumor immune microenvironment, is expected in the coming years.

Noninvasive Immunotyping and Immunotherapy Monitoring of Lung Cancers via Nuclear Imaging of LAG-3 and PD-L1.

Immunotherapy has significantly improved cancer patient survival, while its efficacy remains limited due to the reliance on a single marker like PD-L1 as well as its spatiotemporal heterogeneity. To address this issue, combining lymphocyte activation gene-3 (LAG-3) with PD-L1 is proposed for identifying immunotypes and monitoring immunotherapy through nuclear imaging. In short, 99mTc-HYNIC-αLAG-3 and 99mTc-HYNIC-αPD-L1 probes are synthesized using anti-human LAG-3 and PD-L1 antibodies, respectively. With high radiochemical purity and in vitro stability, these probes are confirmed to specifically bind to LAG-3 or PD-L1 in LAG3+ A549, LAG3- A549, and H1975 cells. SPECT/CT imaging of both probes showed specific in vivo tumor uptake in multiple lung cancer models, with significant linear correlation with ex vivo tumor uptake and immunohistochemical expression levels of LAG-3/PD-L1. Based on this, dual-index imaging was performed to simultaneously quantify LAG-3 and PD-L1. SPECT/CT imaging of 99mTc-HYNIC-αLAG-3 and 125I-αPD-L1 successfully distinguished four immunotypes. In addition, SPECT/CT imaging revealed LAG-3 upregulation in LLC-bearing LAG-3 humanized mice resistant to immunotherapy. In conclusion, this study demonstrates the feasibility of nuclear imaging of LAG-3 and PD-L1 for both noninvasive immunotyping and immunotherapy monitoring, thus offering novel perspectives on forecasting immunotherapy response, uncovering resistance mechanism, and optimizing combination treatment regimens.

Next Generation of Solid Target Radionuclide Antibody Conjugates for Tumor Immuno-Therapy.

Immune checkpoint therapy has emerged as an effective treatment option for various types of cancers. Key immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and lymphocyte activation gene 3 (LAG-3), have become pivotal targets in cancer immunotherapy. Antibodies designed to inhibit these molecules have demonstrated significant clinical efficacy. Nevertheless, the ability to monitor changes in the immune status of tumors and predict treatment response remains limited. Conventional methods, such as assessing lymphocytes in peripheral blood or conducting tumor biopsies, are inadequate for providing real-time, spatial information about T-cell distributions within heterogeneous tumors. Positron emission tomography (PET) using T-cell specific probes represents a promising and noninvasive approach to monitor both systemic and intratumoral immune changes during treatment. This technique holds substantial clinical significance and potential utility. In this paper, we review the applications of PET probes that target immune cells in molecular imaging.

A Novel Subset of Regulatory T Cells Induced by B Cells Alleviate the Severity of Immunological Diseases.

Regulatory T (Treg) cells are crucial for maintaining immune tolerance by suppressing response to self-antigens and harmless antigens to prevent autoimmune diseases and uncontrolled immune responses. Therefore, using Treg cells is considered a therapeutic strategy treating inflammatory diseases. Based on their origin, Treg cells are classified into thymus-derived, peripherally induced, and in vitro induced Treg cells. Our group discovered a novel Treg cell subset, namely, Treg-of-B (Treg/B) cells, generated by culturing CD4+CD25- T cells with B cells, including Peyer's patch B cells, splenic B cells and peritoneal B1a cells, for 3days. Treg/B cells express CD44, OX40 (CD134), cytotoxic T-lymphocyte-associated antigen-4 (CD152), glucocorticoid-induced tumor necrosis factor receptor family-related protein (CD357), interleukin-10 receptor, lymphocyte activation gene-3 (CD223), inducible co-stimulator (CD278), programmed-death 1 (CD279), tumor necrosis factor receptor II, and high levels of IL-10, but not forkhead box protein P3, similar to type 1 Treg (Tr1) cells. However, unlike Tr1 cells, Treg/B cells do not express CD103, CD226, and latency-associated peptide. Treg/B cells have been applied for the treatment of some murine models of inflammatory diseases, including allergic asthma, inflammatory bowel disease, collagen-induced arthritis, gout, psoriasis and primary biliary cholangitis. This review summarizes the current knowledge of Treg/B cells.

Pan-cancer and single-cell analysis reveal dual roles of lymphocyte activation gene-3 (LAG3) in cancer immunity and prognosis

Lymphocyte activating gene-3 (LAG3) is a distinctive T cell co-receptor that is expressed on the surface of lymphocytes. It plays a special inhibitory immune checkpoint role due to its unique domain and signaling pattern. Our aim is to explore the correlation between LAG3 in cancers and physiological processes related to a range of cancers, as well as build LAG3-related immunity and prognostic models. By comprehensively using of datasets and methods from TCGA, GTE-x and GEO databases, cBioPortal, HPA, Kaplan-Meier Plotter, Spearman, CellMinerTM, we delved deeper into the potential impact of the LAG3 in cancer development. These include expression differences, Localization of tumor cell subsets, immune infiltration, matrix infiltration, gene mutations, DNA methylation, signaling pathways and prognosis. Furthermore, we explored LAG3 interactions with different drugs. LAG3 is highly expressed in ACC (p < 0.001), BRCA (p < 0.001), DLBC (p < 0.001), ESCA (p < 0.001), GBM (p < 0.001), HNSC (p < 0.001), KIRC (p < 0.001), LGG (p < 0.001), LUAD (p < 0.01), LUSC (p < 0.001), PAAD (p < 0.001), PCPG (p < 0.01), SKCM (p < 0.001), STAD (p < 0.001), TGCT (p < 0.001) and THCA (p < 0.05), while lowly expressed in COAD (p < 0.001), LIHC (p < 0.05), OV (p < 0.001), PRAD (p < 0.001), READ (p < 0.001), UCEC (p < 0.001) and UCS (p < 0.001). High expression of LAG3 correlates with longer overall survival (OS) in BLCA (HR = 0.67, p < 0.05), CESC (HR = 0.3, p < 0.001), HNSC (HR = 0.67, p < 0.01), LUSC (HR = 0.71, p < 0.05), OV (HR = 0.65, p < 0.01), STAD (HR = 0.68, p < 0.05), and UCEC (HR = 0.57, p < 0.01). Conversely, in KIRC (HR = 1.85, p < 0.001), KIRP (HR = 2.81, p < 0.001), and THYM (HR = 8.92, p < 0.001), high LAG3 expression corresponds to shorter OS. Comprehensive results for recurrence-free survival (RFS) indicate that LAG3 acts as a protective factor in BLCA, CESC, OV, and UCEC. Moreover, LAG3 is widely expressed in tumor-associated lymphocytes, positively correlating with tumor immune scores and stromal scores, and significantly present in the C2 immune subtype across various tumors. High LAG3 expression correlates with increased immune infiltration. LAG3 shows associations with MSI, TMB, and the MMR system, participating in multiple signaling pathways including the T cell receptor pathway. It also demonstrates positive correlations with sensitivity to eleven different drugs. Unlike traditional inhibitory immune checkpoints, LAG3 exhibits dual roles in clinical and immune prognostication across pan-cancers, making it a significant predictive factor. In some cancers, LAG3 serves as a risk factor, indicating adverse clinical outcomes. Conversely, in BLCA, CESC, OV, and UCEC, LAG3 acts as a protective factor associated with longer patient survival. LAG3 demonstrates strong associations within tumor immunity, participating in a range of immune and inflammatory signaling pathways. Elevated levels of LAG3 are linked not only to T cell exhaustion but also to increased immune infiltration and polarization towards M1 macrophages.

Anti-tumor effects of recombinant human cyclophilin A combined with immune checkpoint inhibitors in the experimental model of melanoma B16 in vivo

Introduction. Immune checkpoint inhibitors have an exceptional position in cancer immunotherapy. Currently, anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and anti-PD-1/PD-L1 (PD-1 – programmed cell death 1, PD-L1 – programmed death 1 ligand 1) therapies are most widely applied in clinical practice. Still, immune checkpoint inhibitors therapy is not always successful, and multiple studies have indicated that it should be combined with other immunotherapeutic strategies, including cytokines. Secreted cyclophilin A (CypA) could be of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Studies of rhCypA as an anti-cancer factor pointed to its potential use in cancer chemoimmunotherapy and combination immunotherapy.Aim. To evaluate anti-tumor effects of combined immunotherapy using rhCypA and immune checkpoint inhibitors in the mouse model of melanoma B16 in vivo.Materials and methods. C57BL/6 mice were subcutaneously transplanted with melanoma B16. On days 6 and 9 posttumor transplantation, monoclonal antibodies to PD-1, PD-L1 and programmed cell death 1 ligand 2 (PD-L2), CTLA-4, lymphocyte-activation gene 3 (LAG-3), or CD276 were intravenously injected into mice at a dose of 100 μg/mouse. RhCypA was injected s/c on days 6–10 post-tumor transplantation at a dose of 100 μg/mouse. The therapeutic effects of combined immunotherapy were evaluated by melanoma B16 growth dynamics and the survival of tumor-bearing mice.Results. In combination with anti-CTLA-4 monoclonal antibodies, rhCypA had the most distinct and prolonged synergic anti-tumor effects until day 19 post-immunotherapy, with an increase in animal lifespan of 70 %. When used with anti-LAG-3 monoclonal antibodies, rhCypA exhibited a synergic therapeutic effect by day 12 post-therapy. Combination of rhCypA with anti-PD-L1 or anti-CD276 monoclonal antibodies had short-term synergic effects until day 5 after therapy. Recombinant human CypA impeded the anti-tumor effects of dual anti-PD-1 + anti-LAG-3 therapy.Conclusion. Our findings pointed out that rhCypA could significantly improve therapeutic effects of individual immune checkpoint inhibitors. Therefore, rhCypA could be potentially proposed as a component of combined anti-tumor immunotherapy.

The FGL-1/LAG-3 Axis is Associated With Disease Course in Alcohol-associated Hepatitis: A Preliminary Report

BackgroundAlcohol-associated hepatitis (AH) has a short-term mortality rate of up to 40% primarily related to impaired hepatocyte regeneration and uncontrolled liver inflammation. The acute phase protein fibrinogen-like protein 1 (FGL-1) produced by hepatocytes stimulates hepatocyte proliferation by autocrine signaling. FGL-1 also is a ligand for the inhibitory T cell receptor lymphocyte activation gene 3 (LAG-3). In these ways, FGL-1 and LAG-3 have beneficial interactions that could be interrupted in AH. We aimed to characterize FGL-1 and LAG-3 in patients with AH and describe their relationship with the disease state and course. MethodsThirty-two patients with AH were included at diagnosis and followed up for 3 years. We measured the hepatic gene expression of FGL-1 and LAG-3 using RNA sequencing, plasma FGL-1 and soluble (s)LAG-3 using ELISA, and LAG-3+CD8+ T cells using flow cytometry. Healthy persons (HC) and patients with stable alcohol-associated cirrhosis served as controls. ResultsAt diagnosis of AH, liver FGL-1 mRNA was increased when compared to HC, whereas plasma FGL-1 was unchanged. In contrast, liver LAG-3 mRNA was reduced in AH. Plasma sLAG-3 levels and the frequency of LAG-3+CD8+ T cells were as in HC. However, those patients who had the lowest plasma FGL-1 and the lowest frequency of LAG-3+CD8+ T cells at diagnosis had the highest disease severity and mortality. ConclusionsOur data suggest that an impaired FGL-1/LAG-3 axis may be involved in the pathogenesis and course of AH.

Monoclonal Antibody against Porcine LAG3 Inhibits Porcine Reproductive and Respiratory Syndrome Virus Infection

Lymphocyte activation gene 3 (LAG3) is an inhibitory receptor and the interaction between fibrinogen-like protein 1 and LAG3 can inhibit the anti-tumor effect of T cells both in vivo and in vitro, which was regarded as a new immune evasion mechanism. Porcine reproductive and respiratory syndrome (PRRS), caused by PRRSV, is an infectious disease characterized by reproductive disorders in pregnant sows and gilts and respiratory problems in pigs of all ages, seriously impacting the pig industry worldwide. In this study, monoclonal antibodies (mAbs) against porcine LAG3 (pLAG3) were developed, and one mAb (1C2) showed good reactivity with pLAG3 on PHA-activated porcine peripheral blood lymphocytes. Epitope mapping showed the epitope recognized by mAb 1C2 was located at amino acid residues 214–435 of pLAG3. LAG3 expression in the tissues of PRRSV-infected pigs was detected, using mAb 1C2 as the primary antibody, and the results revealed that PRRSV infection caused a marked increase in LAG3 expression compared to the control group. Interference of LAG3 expression on PHA-activated lymphocytes promoted PRRSV replication in the co-culture system of monocyte-derived dendritic cells and lymphocytes, whereas overexpression of LAG3 or blocking of the LAG3 signal with mAb 1C2 inhibited PRRSV replication, indicating that PRRSV infection activates the LAG3-signaling pathway, suggesting that this pathway plays an important role in PRRSV pathogenesis. The results obtained lay the foundation for subsequent research on the role of LAG3 in PRRS and other diseases with persistent infection characteristics.

6529 The Risk of Hypophysitis Following Treatment With Relatlimab+Nivolumab Appears Higher Than Expected

Abstract Disclosure: N. Chamorro-Pareja: None. A.T. Faje: None. K.K. Miller: Stock Owner; Self; Bristol-Myers Squibb. Hypophysitis is a recognized complication of immune checkpoint inhibitor therapy; the risk of developing hypophysitis in patients receiving nivolumab (an anti-programmed death-ligand 1 [anti-PD-1]) is estimated to be &amp;lt; 1%. Relatlimab is a human monoclonal antibody targeting lymphocyte activation gene 3 (LAG-3) recently approved in combination with nivolumab for the treatment of unresectable or metastatic melanoma. The risk of hypophysitis as a complication of relatlimab therapy is not well-defined. Objective: To examine the prevalence, identify risk factors, and characterize the clinical presentation of hypophysitis in patients receiving relatlimab+nivolumab. Methods: 159 patients received relatlimab+nivolumab at the Mass General Brigham health care system between 6/2015 and 11/2023. Twenty-seven patients were excluded because they were either diagnosed with adrenal insufficiency (AI) before receiving relatlimab+nivolumab or AI was secondary to other factors, primarily exogenous glucocorticoid administration, leaving a total of 122 patients. The medical records of these patients, including provider encounters, laboratory results, medication records, and radiologic images were reviewed. Data are presented as mean ± SD. Results: Central AI was diagnosed in 10 patients (7.5% of the cohort) after relatlimab+nivolumab administration. The mean age was 64.5±13.8 vs. 67.1±14.4 in patients with AI vs. patients without AI (p= 0.58). Sixty percent of patients in the AI group were male compared to 53% of patients without AI (p= 0.68). The development of AI was not related to the cumulative dose of relatlimab+nivolumab (mean number of cycles 6.4±3.2 vs. 4.9±5.0, p=0.35). The most common presenting symptoms of AI were fatigue, anorexia, nausea, and vomiting. No patients were diagnosed with additional anterior pituitary hormone deficiencies, though not all patients were evaluated for these diagnoses; none had diabetes insipidus. Nine patients had MRIs performed after the diagnosis of central AI; 7 of these patients had pre-treatment MRIs for comparison. Diffuse pituitary enlargement was seen on MRI after initiation of relatlimab+nivolumab in 3 patients up to 8 weeks prior to the diagnosis of hypopituitarism. All patients had persistent hypopituitarism at the most recent evaluation. Conclusions: This study is the first cohort analysis of hypophysitis in patients treated with relatlimab+nivolumab. A significant portion of patients were diagnosed with central AI, presumptively due to hypophysitis given the lack of an identifiable alternative etiology. Although the clinical phenotype of these patients paralleled published studies analyzing anti-PD-1 monotherapy, combination treatment with relatlimab+nivolumab appeared to confer a significantly higher risk of developing hypophysitis. Presentation: 6/3/2024

Anti-metabolite chemotherapy increases LAG-3 expressing tumor-infiltrating lymphocytes which can be targeted by combination immune checkpoint blockade

BackgroundAntibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein/ligand 1 (PD-1/PD-L1) are approved for treatment of multiple cancer types. Chemotherapy is often...

Exploring the molecular landscape of lymphocyte activation gene-3: A literature review.

Molecular structure and cellular distribution of lymphocyte activation gene-3 (LAG-3) have been studied extensively since 1990. However, several unresolved questions remain. It is well-established that LAG-3 plays a significant role in maintaining immune homeostasis. The presence of deficiencies in LAG-3 has been observed to be linked with autoimmune disorders, whereas the excessive expression of LAG-3 within the tumor microenvironment hinders immune responses, particularly those mediated by lymphocytes, thereby facilitating immune evasion. Consequently, investigations into these 2 aspects have become a prominent focus in both fundamental and clinical research. The objective of this review is to examine the functions and molecular characteristics of LAG-3, as well as its current clinical applications in the context of tumor immune escape and autoimmune disease. The ultimate aim is to explore and propose novel immune therapy approach.

Lymphocyte Function in Tertiary Lymphoid Structures Predicts Hepatocellular Carcinoma Outcome

An increasing number of studies have revealed a correlation between tertiary lymphoid structures (TLSs) and the outcome of hepatocellular carcinoma (HCC). Nevertheless, the associations between the heterogeneity of cellular composition and the overall survival (OS) in HCC remain unexplored. Here, we evaluated the cancer tissues from 150 HCC individuals treated at the Tumor Hospital Affiliated with Nantong University using multiplex immunofluorescence to determine the presence and characteristics of TLS and to investigate the relationship between intra-TLS immunologic activity, TLS maturation, and intratumoral immune cell infiltration. Prognostic factors influencing the outcome were identified through both univariate and multivariate analyses. Additionally, the levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death 1, programmed death-ligand 1, and lymphocyte activation gene-3 were determined, as well as their relationship with TLS features were determined. TLS was detected in 71 (47.3%) of the 150 HCC cases and was related to higher intratumoral infiltration levels of lymphocytes. Additionally, intra-TLS lymphocyte proliferation correlated with that of intratumoral lymphocytes, and the presence of TLS and a high proportion of mature TLS demonstrated a significant correlation with better prognosis (P = .013 and P = .03, respectively). Among TLS-positive tumors, a high proportion of B cells expressing activation-induced cytidine deaminase and a high proportion of CD8+ T cells expressing CD45RO were significantly related to improved OS (P = .01 and P < .001, respectively). Comparatively, a high proportion of CD21+CD20+ B cells demonstrated a significant correlation with poorer OS (P < .002). A markedly reduced number of CTLA-4+ cells in the stromal regions in TLS-negative tumors was observed compared with TLS-positive tumors (P = .01). These findings reveal a correlation between TLS presence and improved OS in HCC patients. However, TLS exhibited significant variation in maturation state, T- and B-cell proliferation, and expression of markers related to B- and T-cell function. Notably, these characteristics were also found to possess prognostic significance, indicating that certain TLS might hinder tumor immunity by inhibiting immune cells, whereas others may foster antigen-driven immune responses, likely influenced by the composition and functional status of intra-TLS lymphocytes.

Design and Biophysical Characterization of Second-Generation cyclic peptide LAG-3 inhibitors for cancer immunotherapy

Lymphocyte activation gene 3 (LAG-3) is an inhibitory immune checkpoint crucial for suppressing the immune response against cancer. Blocking LAG-3 interactions enables T cells to recover their cytotoxic capabilities and diminishes the immunosuppressive effects of regulatory T cells. A cyclic peptide (Cys-Val-Pro-Met-Thr-Tyr-Arg-Ala-Cys, disulfide bridge: 1–9) was recently reported as a LAG-3 inhibitor. Based on this peptide, we designed 19 derivatives by substituting tyrosine residue to maximize LAG-3 inhibition. Screening via TR-FRET assay identified 8 outperforming derivatives, with cyclic peptides 12 [Tyr6(L-3-CN-Phe)], 13 [Tyr6(L-4-NH2-Phe)], and 17 [Tyr6(L-3,5-DiF-Phe)] as top candidates. Cyclic peptide 12 exhibited the highest inhibition (IC50 = 4.45 ± 1.36 µM). MST analysis showed cyclic peptides 12 and 13 bound LAG-3 with KD values of 2.66 ± 2.06 µM and 1.81 ± 1.42 µM, respectively, surpassing the original peptide (9.94 ± 4.13 µM). Docking simulations revealed that cyclic peptide 12 exhibited significantly enhanced binding, with a docking score of −7.236 kcal/mol, outperforming the original peptide (−5.236 kcal/mol) and cyclic peptide 5 (L-4-CN-Phe) (−5.131 kcal/mol). A per-residue decomposition of the interaction energy indicated that the 3-cyano group in cyclic peptide 12 contributes to a more favorable conformation, yielding an interaction energy of −9.22 kcal/mol with Phe443 of MHC-II, compared to −6.03 kcal/mol and −5.619 kcal/mol for cyclic peptides 0 and 5, respectively. Despite promising in vitro results, cyclic peptide 12 failed to inhibit tumor growth in vivo, underscoring the importance of dual immunotherapies targeting several immune checkpoints to achieve anti-tumor efficacy.

Novel Immune Checkpoint Inhibitor Targets in Advanced or Metastatic Renal Cell Carcinoma: State of the Art and Future Perspectives.

Immune checkpoint inhibitors (ICI) have become the cornerstone of treatment in renal cell carcinoma (RCC), for both metastatic disease and in an adjuvant setting. However, an adaptive resistance from cancer cells may arise during ICI treatment, therefore many studies are focusing on additional immune checkpoint inhibitor pathways. Promising targets of immunotherapeutic agents under investigation include T cell immunoglobulin and ITIM domain (TIGIT), immunoglobulin-like transcript 4 (ILT4), lymphocyte activation gene-3 (LAG-3), vaccines, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and chimeric antigen receptor (CAR) T cells. In this review of the literature, we recollect the current knowledge of the novel treatment strategies in the field of immunotherapy that are being investigated in RCC and analyze their mechanism of action, their activity and the clinical studies that are currently underway.

Real-world treatment patterns and outcomes of patients with advanced melanoma treated with nivolumab plus relatlimab

Abstract The use of programmed death-1 (PD-1) inhibitors has been a pivotal advancement in treating advanced melanoma, yet their efficacy is limited. The approval of relatlimab (RELA), a lymphocyte activation gene 3 protein (LAG-3) antibody, in combination with nivolumab (NIVO), a PD-1 inhibitor, marked a significant stride toward enhancing treatment efficacy for metastatic and unresectable stage 3 and 4 melanoma. This combination has been shown to synergistically improve antitumor activity and effector T-cell activity in the tumor microenvironment, despite limited data on real-world outcomes. Our retrospective review at a tertiary cancer center of patients with stage 3 and 4 melanoma treated with NIVO-RELA revealed an overall response rate (ORR) of 39%, with notable improvements in median PFS and ORR, especially in first-line treated patients. Our study highlights the superior efficacy of NIVO-RELA over previous reports, demonstrating its significant potential in the treatment landscape of advanced melanoma.

Revolutionizing Skin Cancer Treatment: The Rise of PD-1/PDL-1 and CTLA-4 as Key Therapeutic Targets.

Skin cancer is a significant health concern, affecting millions of individuals globally on an annual basis. According to data from the World Health Organization, it stands as the most prevalent form of cancer within the white population. Current treatments for skin cancer typically involve a combination of chemotherapy, radiation therapy, and surgery. However, these methods often come with drawbacks, such as side effects and potential scarring. Therefore, there is a growing need for alternative treatments that can offer effective results with fewer adverse effects, driving ongoing research in skin cancer therapy. The advancement of immune checkpoint inhibitors has been facilitated by a more profound comprehension of the interplay between tumors and the immune system, along with the regulatory mechanisms governing T-cells. As cancer treatment continues to evolve, immunotherapy is emerging as a powerful strategy, leading to a growing interest in the role of immunological checkpoints in skin cancer. Various types of immune checkpoints and their expression, including PD-1, PDL-1, CTLA-4, lymphocyte activation gene 3, and B7-H3, along with their blockers and monoclonal antibodies, have been established for various cancers. PD-1, PDL-1, and CTLA-4 are crucial immune system regulators, acting as brakes to prevent T-- cell overactivation and potential autoimmunity. However, tumors can exploit these checkpoints to evade immune detection. Inhibiting these immune checkpoints can enhance the body's ability to recognize and attack cancer cells. This review focuses on the characteristics of PD-1, PDL-1, and CTLA-4 immune checkpoints, their mechanism of action, and their role in skin cancer. Additionally, it summarizes the ongoing clinical trials sponsored or conducted by various pharmaceutical companies and provides insights into the latest patent data.

Immuno-related cardio-vascular adverse events associated with immuno-oncological treatments: an under-estimated threat for cancer patients.

Immunotherapy represents an emergent and heterogeneous group of anticancer treatments harnessing the human immune-surveillance system, including immune-checkpoint inhibitor monoclonal antibodies (mAbs), Chimeric Antigen Receptor T Cells (CAR-T) therapy, cancer vaccines and lymphocyte activation gene-3 (LAG-3) therapy. While remarkably effective against several malignancies, these therapies, often in combination with other cancer treatments, have showed unforeseen toxicity, including cardiovascular complications. The occurrence of immuno-mediated adverse (irAEs) events has been progressively reported in the last 10years. These irAEs present an extended range of severity, from self-limiting to life-threatening conditions. Although recent guidelines in CardioOncology have provided important evidence in managing cancer treatments, they often encompass general approaches. However, a specific focus is required due to the particular etiology, unique risk factors, and associated side effects of immunotherapy. This review aims to deepen the understanding of the prevalence and nature of cardiovascular issues in patients undergoing immunotherapy, offering insights into strategies for risk stratification and management.

Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming

Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated Tcells and has been proposed to regulate regulatory T (Treg) cell function. However, its precise modality and mechanisms remain elusive. We generated Treg cell-specific Lag3-mutant mouse models and found that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3-mutant Treg cells was increased to the level seen in conventional T helper (Th)1-type effector cells and directly correlated with their metabolic profiles and invivo suppressive functions. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells, and inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme converting pyruvate to lactate, was sufficient to restore normal metabolism and suppressive function in Lag3-mutant Treg cells. These findings indicate that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming.

CD8+ T cell‑related KCTD5 contributes to malignant progression and unfavorable clinical outcome of patients with triple‑negative breast cancer.

Triple‑negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of breast cancer that lacks expression of estrogen receptor, progesterone receptor, and HER2, making it more challenging to treat with targeted therapies. The present study aimed to identify CD8+ T cell‑associated genes, which could provide insight into the mechanisms underlying TNBC to facilitate developing novel immunotherapies. TNBC datasets were downloaded from public databases including The Cancer Genome Atlas, Molecular Taxonomy of Breast Cancer International Consortium, and Gene Expression Omnibus. Candidate genes were identified integrating weighted gene co‑expression network analysis (WGCNA), differential gene expression, protein‑protein‑interaction network construction and univariate Cox regression analysis. Kaplan‑Meier survival, multivariate Cox regression and receiver operating characteristic analysis were performed to evaluate the prognostic value of hub genes. Knockdown experiments, alongside wound healing, Cell Counting Kit‑8 and Transwell migration and invasion assays were performed. In total, seven gene modules were associated with CD8+ T cells using WGCNA, among which potassium channel tetramerization domain 5 (KCTD5) was significantly upregulated in TNBC samples and was associated with poor prognosis. KCTD5 expression inversely associated with infiltration ratios of 'Macrophages M1', 'Plasma cells', and 'γδ T cells', but positively with 'activated Mast cells', 'Macrophages M0', and 'Macrophages M2'. As an independent prognostic indicator for TNBC, KCTD5 was also associated with drug sensitivity and the expression of programmed cell death protein 1, Cytotoxic T‑Lymphocyte‑Associated Protein 4 (CTLA4), CD274), Cluster of Differentiation 86 (CD86), Lymphocyte‑Activation Gene 3 (LAG3), T Cell Immunoreceptor with Ig and ITIM Domains (TIGIT). Knockdown of KCTD5 significantly inhibited viability, migration and invasion of TNBC cells in vitro. KCTD5 was suggested to impact the tumor immune microenvironment by influencing the infiltration of immune cells and may serve as a potential therapeutic target for TNBC.

Sepsis-Induced Immunosuppression: The Role of Co-inhibitory Molecules

Sepsis is one of the most common cause of death among hospitalized patients in the intensive care unit (ICU), with current therapeutic options falling short of a comprehensive solution. The condition&amp;apos;s pathophysiology is marked by a spectrum of immunological impairments, with a growing consensus that immunosuppression plays a decisive role in the condition&amp;apos;s rising morbidity and mortality rates. Extensive preclinical and clinical research has identified the upregulation of several co-inhibitory molecules during sepsis, including Programmed Death-1 (PD-1), Programmed Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), B and T Lymphocyte Attenuator (BTLA), T Cell Membrane Protein-3 (TIM-3), and Lymphocyte Activation Gene-3 (LAG-3). These molecules, which exert a significant inhibitory effect on T cell function, are believed to contribute to the immunosuppressive state induced by sepsis. The elucidation of the intricate mechanisms by which these molecules induce immunosuppression is essential for devising the most efficacious treatment strategies for sepsis. The burgeoning field of immunotherapy, particularly the blockade of co-inhibitory molecules, represents a significant frontier in sepsis research. This approach holds substantial promise for the future of sepsis therapy, warranting further exploration and clinical investigation to harness its potential fully.