ABSTRACT
Anti-CTLA-4 antibodies faced challenges due to frequent adverse events and limited efficacy, which spurred the exploration of next-generation CTLA-4 therapeutics to balance regulatory T cells (Tregs) depletion and CD8 T cells activation. CCR8, identified primarily on tumor-infiltrating Tregs, has become a target of interest due to the anti-tumor effects demonstrated by CCR8 antibody-mediated Tregs depletion. Single-cell RNA sequencing analysis reveals that CCR8-positive Tregs constitute a small subset, with concurrent expression of CCR8 and CTLA-4. Consequently, we proposed a novel bispecific antibody targeting CCR8 and CTLA-4 that had the potential to enhance T cell activation while selectively depleting intratumor Tregs. The candidate molecule 2MW4691 was developed in a tetravalent symmetric format, maintaining a strong binding affinity for CCR8 while exhibiting relatively weaker CTLA-4 binding. This selective binding ability allowed 2MW4691 to target and deplete tumor-infiltrating Tregs with higher specificity. In vitro assays verified the antibody's capacity for antibody-dependent cellular cytotoxicity (ADCC) to Tregs with high level of CTLA-4 expression, but not CD8 T cells with relatively low level of CTLA-4 on cell surface. Also, 2MW4691 inhibited the CTLA-4 pathway and enhanced T cell activation. The in vivo therapeutic efficacy of 2MW4691 was further demonstrated using hCCR8 or hCTLA-4 humanized mouse models and hCCR8/hCTLA-4 double knock-in mouse models. In cynomolgus monkeys, 2MW4691 was well-tolerated, exhibited the anticipated pharmacokinetic profile, and had a minimal impact on the peripheral T cell population. The promising preclinical results supported the further evaluation of 2MW4691 as a next-generation Treg-based therapeutics in clinical trials.
Subject(s)
Antibodies, Bispecific , CD8-Positive T-Lymphocytes , CTLA-4 Antigen , T-Lymphocytes, Regulatory , Animals , Mice , Antibodies, Bispecific/pharmacology , Antibodies, Bispecific/immunology , Antibodies, Bispecific/therapeutic use , Humans , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , T-Lymphocytes, Regulatory/immunology , CD8-Positive T-Lymphocytes/immunology , Receptors, CCR8/immunology , Neoplasms/immunology , Neoplasms/drug therapy , Neoplasms/therapy , Signal Transduction/drug effects , Female , Xenograft Model Antitumor Assays , Macaca fascicularisABSTRACT
Although immune checkpoint inhibitors (anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody) have displayed considerable success in the treatment of malignant tumors, the therapeutic effect is still unsatisfactory for a portion of patients. Therefore, it is imperative to develop strategies to enhance the effect of these ICIs. Increasing evidence strongly suggests that the key to this issue is to transform the tumor immune microenvironment from a state of no or low immune infiltration to a state of high immune infiltration and enhance the tumor cell-killing effect of T cells. Therefore, some combination strategies have been proposed and this review appraise a summary of 39 strategies aiming at enhancing the effectiveness of ICIs, which comprise combining 10 clinical approaches and 29 foundational research strategies. Moreover, this review improves the comprehensive understanding of combination therapy with ICIs and inspires novel ideas for tumor immunotherapy.
Subject(s)
B7-H1 Antigen , CTLA-4 Antigen , Immune Checkpoint Inhibitors , Neoplasms , Programmed Cell Death 1 Receptor , Humans , Neoplasms/immunology , Neoplasms/drug therapy , Neoplasms/therapy , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Immunotherapy/methods , Tumor Microenvironment/immunology , Animals , Treatment OutcomeABSTRACT
Breast cancer (BC) has a high mortality rate and is one of the most common malignancies in the world. Initially, BC was considered non-immunogenic, but a paradigm shift occurred with the discovery of tumor-infiltrating lymphocytes (TILs) and regulatory T cells (Tregs) in the BC tumor microenvironment. CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) immunotherapy has emerged as a treatment option for BC, but it has limitations, including suboptimal antitumor effects and toxicity. Research has demonstrated that anti-CTLA-4 combination therapies, such as Treg depletion, cancer vaccines, and modulation of the gut microbiome, are significantly more effective than CTLA-4 monoclonal antibody (mAB) monotherapy. Second-generation CTLA-4 antibodies are currently being developed to mitigate immune-related adverse events (irAEs) and augment antitumor efficacy. This review examines anti-CTLA-4 mAB in BC, both as monotherapy and in combination with other treatments, and sheds light on ongoing clinical trials, novel CTLA-4 therapeutic strategies, and potential utility of biomarkers in BC.
Subject(s)
Breast Neoplasms , CTLA-4 Antigen , Humans , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Breast Neoplasms/immunology , Breast Neoplasms/therapy , Female , Immunotherapy/methods , Tumor Microenvironment/immunology , Antibodies, Monoclonal/therapeutic use , T-Lymphocytes, Regulatory/immunology , Lymphocytes, Tumor-Infiltrating/immunologyABSTRACT
Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen. Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti- CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects. Results: Tumors with volumes of 2,000 mm3 or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory. Conclusions: These findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors.
Subject(s)
Immunotherapy , Animals , Mice , Immunotherapy/methods , Cell Line, Tumor , Female , Combined Modality Therapy , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/immunology , Interleukin-12 , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Radioimmunotherapy/methods , Interleukin-2 , Mice, Inbred BALB C , Immunologic Memory , Neoplasm Staging , Colonic Neoplasms/therapy , Colonic Neoplasms/immunology , Colonic Neoplasms/pathologyABSTRACT
Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells.
Subject(s)
B7-H1 Antigen , Carcinoma, Squamous Cell , Cell Plasticity , Epithelial-Mesenchymal Transition , Immune Checkpoint Inhibitors , Immunotherapy , Skin Neoplasms , Animals , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Skin Neoplasms/therapy , Skin Neoplasms/drug therapy , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/drug therapy , Mice , Humans , B7-H1 Antigen/metabolism , B7-H1 Antigen/antagonists & inhibitors , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Male , Immunotherapy/methods , Epithelial-Mesenchymal Transition/immunology , Cell Plasticity/drug effects , Cell Line, Tumor , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/metabolism , CTLA-4 Antigen/immunology , Receptors, Virus/metabolism , Receptors, Virus/genetics , B7-1 Antigen/metabolism , Receptors, Immunologic/metabolismABSTRACT
Infection with severe acute respiratory syndrome coronavirus 2 (SARSCoV2) triggers coronavirus disease 2019 (COVID-19), which predominantly targets the respiratory tract. SARS-CoV-2 infection, especially severe COVID-19, is associated with dysregulated immune responses against the virus, including exaggerated inflammatory responses known as the cytokine storm, together with lymphocyte and NK cell dysfunction known as immune cell exhaustion. Overexpression of negative immune checkpoints such as PD-1 and CTLA-4 plays a considerable role in the dysfunction of immune cells upon SARS-CoV-2 infection. Blockade of these checkpoints has been suggested to improve the clinical outcome of COVID-19 patients by promoting potent immune responses against the virus. In the current review, we provide an overview of the potential of checkpoint inhibitors to induce potent immune responses against SARS-CoV-2 and improving the clinical outcome of severe COVID-19 patients.
Subject(s)
COVID-19 Drug Treatment , COVID-19 , Immune Checkpoint Inhibitors , SARS-CoV-2 , Humans , Immune Checkpoint Inhibitors/therapeutic use , COVID-19/immunology , SARS-CoV-2/immunology , Animals , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunologyABSTRACT
Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether CTLA-4 or PD-1 blockade. The frequency of Tregs was significantly decreased with CTLA-4 Ig. The resulting increased CD8/Treg ratio potentially underlies the enhanced efficacy of ICT followed by CTLA-4 Ig. This paradoxical mechanism shows that a CTLA-4 Ig regimen shown to reduce irAE severity does not compromise antitumor efficacy.
Subject(s)
CTLA-4 Antigen , Immunotherapy , Animals , Mice , Immunotherapy/methods , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , CD8-Positive T-Lymphocytes/immunology , T-Lymphocytes, Regulatory/immunology , Cell Line, Tumor , Abatacept/therapeutic use , Abatacept/pharmacology , Female , Humans , Mice, Inbred C57BL , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunologyABSTRACT
INTRODUCTION: Esophageal cancer (EC), particularly esophageal squamous cell carcinoma (ESCC), is characterized by high incidence and poor prognosis worldwide, necessitating novel therapeutic approaches like immunotherapy. This review explores the impact of immune checkpoint inhibitors (ICIs) on ESCC, especially focusing on PD-1/PD-L1 and CTLA-4 inhibitors. Our literature search, conducted across databases including PubMed, Web of Science, and EMBASE, from January 2010 to December 2023, aimed at identifying advancements, challenges, and future directions in the use of immunotherapy for ESCC. AREAS COVERED: We provide a detailed analysis of clinical trials evaluating the efficacy of ICIs as monotherapy and in combination with chemotherapy, radiotherapy, and targeted therapy for locally advanced ESCC. Our findings highlight the significant survival benefits offered by ICIs, albeit with varying efficacy across patient populations, emphasizing the need for precise biomarkers to tailor treatment strategies. EXPERT OPINION: The integration of immunotherapy into the ESCC treatment paradigm represents a significant shift, improving survival outcomes. Future research should focus on optimizing combination therapies and novel immunotherapeutic agents, incorporating genetic and tumor microenvironment analyses to enhance patient selection and treatment efficacy.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Immune Checkpoint Inhibitors , Immunotherapy , Humans , Esophageal Neoplasms/therapy , Esophageal Neoplasms/immunology , Esophageal Squamous Cell Carcinoma/therapy , Esophageal Squamous Cell Carcinoma/immunology , Immunotherapy/methods , Immune Checkpoint Inhibitors/therapeutic use , Tumor Microenvironment/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Combined Modality Therapy , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , AnimalsABSTRACT
Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a heterogeneous disease characterized by local inflammation of the upper airway and sinus mucosa. T cell-mediated immune responses play irreplaceable roles in the pathogenesis of nasal polyps. CD161+ T cells have been implicated in the pathology of several diseases through cytokine production and cytotoxic activity. However, the immunological characteristics of CD161+ T cells in nasal mucosa are still not well understood, particularly in CRSwNPs. Our research revealed a notable enrichment of CD161+ T cells in nasal tissues compared to peripheral blood, with a significantly more infiltration of CD161+ T cells in CRSwNPs compared to control nasal samples. Phenotypical analysis found that CD161+ T cells predominantly co-expressed tissue-resident memory surface markers CD103, CD69, and CD45RO. CD161+CD103+ T cells demonstrated complicated effector functions, marked by elevated levels of PD-1, CTLA-4, IL-17, and IFN-γ and diminished expression of FoxP3 and CD25. Interestingly, despite CD161+ T cells was more abundant in polyp tissues compared to normal control tissues, and then further categorizing polyp samples into distinct groups based on clinical characteristics, only the recurrent CRSwNP group showed a significant reduction in CD161+CD8+ T cells compared to the primary CRSwNP group. This finding suggested the necessity for further research to comprehensively understand the underlying mechanisms and the broader significance of CD161+ T cells in the advancement and relapse of CRSwNPs.
Subject(s)
Antigens, CD , Integrin alpha Chains , NK Cell Lectin-Like Receptor Subfamily B , Nasal Polyps , Rhinosinusitis , Adult , Female , Humans , Male , Middle Aged , Antigens, CD/metabolism , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/metabolism , Antigens, Differentiation, T-Lymphocyte/immunology , Chronic Disease , CTLA-4 Antigen/metabolism , CTLA-4 Antigen/immunology , Integrin alpha Chains/metabolism , Integrin alpha Chains/immunology , Interferon-gamma/metabolism , Interferon-gamma/immunology , Interleukin-17/metabolism , Interleukin-17/immunology , Lectins, C-Type , Nasal Mucosa/immunology , Nasal Polyps/immunology , NK Cell Lectin-Like Receptor Subfamily B/metabolism , NK Cell Lectin-Like Receptor Subfamily B/immunology , Rhinosinusitis/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting T cell (Tc) immunoglobulin and mucin-containing molecule 3 (TIM-3) for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations. Anti-TIM-3 Ab treatment improved survival of mice bearing leukemia with oncogene-induced TIM-3 ligand expression. Conversely, leukemia cells with low ligand expression were anti-TIM-3 treatment resistant. In vitro, TIM-3 blockade or genetic deletion in CD8+ Tc enhanced Tc activation, proliferation, and IFN-γ production while enhancing GVL effects, preventing Tc exhaustion, and improving Tc cytotoxicity and glycolysis in vivo. Conversely, TIM-3 deletion in myeloid cells did not affect allogeneic Tc proliferation and activation in vitro, suggesting that anti-TIM-3 treatment-mediated GVL effects are Tc induced. In contrast to anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) treatment, anti-TIM-3-treatment did not enhance acute graft-versus-host disease (aGVHD). TIM-3 and its ligands were frequently expressed in acute myeloid leukemia (AML) cells of patients with post-allo-HCT relapse. We decipher the connections between oncogenic mutations found in AML and TIM-3 ligand expression and identify anti-TIM-3 treatment as a strategy for enhancing GVL effects via metabolic and transcriptional Tc reprogramming without exacerbation of aGVHD. Our findings support clinical testing of anti-TIM-3 Ab in patients with AML relapse after allo-HCT.
Subject(s)
Hepatitis A Virus Cellular Receptor 2 , Animals , Hepatitis A Virus Cellular Receptor 2/genetics , Hepatitis A Virus Cellular Receptor 2/metabolism , Mice , Hematopoietic Stem Cell Transplantation , Graft vs Leukemia Effect/immunology , Graft vs Leukemia Effect/genetics , Humans , Allografts , Ligands , Oncogenes , CD8-Positive T-Lymphocytes/immunology , Mice, Knockout , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/pathology , CTLA-4 Antigen/genetics , CTLA-4 Antigen/immunology , CTLA-4 Antigen/metabolism , CTLA-4 Antigen/antagonists & inhibitors , Gene Expression Regulation, LeukemicABSTRACT
AIM: To investigate the status of immune checkpoint molecules (CTLA-4 and TIM-3) in meningiomas and thus contribute to the development of new personalized treatment strategies. MATERIAL AND METHODS: We utilized 402 cases of meningioma for this study. New blocks were prepared using the tissue microarray method, and sections obtained from these blocks were immunohistochemically stained with CTLA-4 and TIM-3 antibodies. Subsequently, statistical analysis were performed. RESULTS: Our findings revealed that CTLA-4 expression were observed in 25.1% of meningiomas. CTLA-4 expression and the number of expressing lymphocytes were found to be significantly higher in high-grade tumors and in those with brain invasion. Meningiomas with staining of immune cells with TIM-3 are 3.5%, and the tumor grade was correlated with the number of immune cells expressing TIM-3. CONCLUSION: Immune checkpoint molecules (CTLA-4 and TIM-3) with varying levels of expression can serve as prognostic and predictive biomarkers, as well as important targets for therapy. Drugs developed for CTLA-4 and TIM-3 molecules may prove to be more effective in treating meningiomas with high-grade, brain-invading, spontaneous necrosis, and macronucleolus.
Subject(s)
CTLA-4 Antigen , Hepatitis A Virus Cellular Receptor 2 , Immunohistochemistry , Meningeal Neoplasms , Meningioma , Humans , Meningioma/immunology , Meningioma/pathology , Meningioma/metabolism , Male , Meningeal Neoplasms/immunology , Meningeal Neoplasms/pathology , Meningeal Neoplasms/metabolism , Female , Middle Aged , CTLA-4 Antigen/metabolism , CTLA-4 Antigen/immunology , Hepatitis A Virus Cellular Receptor 2/metabolism , Aged , Adult , Biomarkers, Tumor/metabolism , Immune Checkpoint Proteins/metabolism , Aged, 80 and over , Young Adult , AdolescentABSTRACT
Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response. Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications.
Subject(s)
Immune Checkpoint Inhibitors , Neoplasms , Humans , Neoplasms/drug therapy , Neoplasms/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , AnimalsABSTRACT
Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/ß inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.
Subject(s)
B7-H1 Antigen , HSC70 Heat-Shock Proteins , Lysosomes , HSC70 Heat-Shock Proteins/metabolism , B7-H1 Antigen/metabolism , B7-H1 Antigen/genetics , Lysosomes/metabolism , Animals , Mice , Humans , Female , Cell Line, Tumor , Proteolysis , Endosomes/metabolism , Neoplasms/immunology , Neoplasms/metabolism , HSP90 Heat-Shock Proteins/metabolism , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Mice, Inbred C57BL , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , CTLA-4 Antigen/metabolism , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Cell Membrane/metabolism , Myelin Proteins , MARVEL Domain-Containing ProteinsABSTRACT
The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.
Subject(s)
Neoplasms , Radiotherapy , Tumor Microenvironment , Humans , Neoplasms/radiotherapy , Neoplasms/immunology , Neoplasms/therapy , Tumor Microenvironment/immunology , Tumor Microenvironment/radiation effects , Animals , Radiotherapy/methods , Immunity, Innate/radiation effects , CTLA-4 Antigen/immunology , CTLA-4 Antigen/metabolism , Immune Checkpoint Inhibitors/therapeutic use , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/immunology , B7-H1 Antigen/metabolism , B7-H1 Antigen/immunology , Adaptive ImmunityABSTRACT
CD4+CD25+Foxp3+ regulatory T cells (Tregs), a vital component of the immune system, are responsible for maintaining immune homeostasis and preventing excessive immune responses. This review explores the signaling pathways of the cytokines that regulate Treg cells, including transforming growth factor beta (TGF-ß), interleukin (IL)-2, IL-10, and IL-35, which foster the differentiation and enhance the immunosuppressive capabilities of Tregs. It also examines how, conversely, signals mediated by IL-6 and tumor necrosis factor -alpha (TNF-α) can undermine Treg suppressive functions or even drive their reprogramming into effector T cells. The B7 family comprises indispensable co-stimulators for T cell activation. Among its members, this review focuses on the capacity of CTLA-4 and PD-1 to regulate the differentiation, function, and survival of Tregs. As Tregs play an essential role in maintaining immune homeostasis, their dysfunction contributes to the pathogenesis of autoimmune diseases. This review delves into the potential of employing Treg-based immunotherapy for the treatment of autoimmune diseases, transplant rejection, and cancer. By shedding light on these topics, this article aims to enhance our understanding of the regulation of Tregs by cytokines and their therapeutic potential for various pathological conditions.
Subject(s)
Cytokines , Signal Transduction , T-Lymphocytes, Regulatory , Humans , T-Lymphocytes, Regulatory/immunology , Animals , Cytokines/metabolism , Cytokines/immunology , CTLA-4 Antigen/immunology , CTLA-4 Antigen/metabolism , Neoplasms/immunology , Neoplasms/therapy , Autoimmune Diseases/immunology , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/immunology , Immunotherapy/methodsABSTRACT
Tigilanol tiglate is an oncolytic small molecule that is undergoing clinical trials. A recent study revealed the capacity of this pyroptosis inducer to elicit hallmarks of immunogenic cell death. In addition, intratumoral injection of tigilanol tiglate can sensitize subcutaneous cancers to subsequent immune checkpoint inhibitors targeting CTLA-4 alone or in combination with PD-1.
Subject(s)
Neoplasms , Humans , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/drug therapy , Animals , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Immunogenic Cell Death/drug effects , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Pyroptosis/drug effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacologyABSTRACT
Immune checkpoint inhibitor therapy has dramatically improved patient prognosis, and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma (ESCC) in the past decade. Monoclonal antibodies that selectively inhibit programmed cell death-1 (PD-1) activity has now become standard of care in the treatment of ESCC in metastatic settings, and has a high expectation to provide clinical benefit during perioperative period. Further, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody. Well understanding of the existing evidence of immune-based treatments for ESCC, as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant, adjuvant, and metastatic diseases, may provide future prospects of ESCC treatment for better patient outcomes.
Subject(s)
CTLA-4 Antigen , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Immune Checkpoint Inhibitors , Immunotherapy , Neoadjuvant Therapy , Humans , Esophageal Neoplasms/therapy , Esophageal Neoplasms/immunology , Esophageal Neoplasms/pathology , Esophageal Neoplasms/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Esophageal Squamous Cell Carcinoma/therapy , Esophageal Squamous Cell Carcinoma/immunology , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/drug therapy , Neoadjuvant Therapy/methods , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Immunotherapy/methods , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Treatment Outcome , Chemotherapy, Adjuvant/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prognosis , Neoplasm Recurrence, Local/prevention & control , Neoplasm Recurrence, Local/immunologyABSTRACT
BACKGROUND: Community-acquired pneumonia often stems from the macrolide-resistant strain of Mycoplasma pneumoniae, yet no effective vaccine exists against it. METHODS: This study proposes a vaccine-immunoinformatics strategy for Mycoplasma pneumoniae and other pathogenic microbes. Specifically, dominant B and T cell epitopes of the Mycoplasma pneumoniae P30 adhesion protein were identified through immunoinformatics method. The vaccine sequence was then constructed by coupling with CTLA-4 extracellular region, a novel molecular adjuvant for antigen-presenting cells. Subsequently, the vaccine's physicochemical properties, antigenicity, and allergenicity were verified. Molecular dynamics modeling was employed to confirm interaction with TLR-2, TLR-4, B7-1, and B7-2. Finally, the vaccine underwent in silico cloning for expression. RESULTS: The vaccine exhibited both antigenicity and non-allergenicity. Molecular dynamics simulation, post-docking with TLR-2, TLR-4, B7-1, and B7-2, demonstrated stable interaction between the vaccine and these molecules. In silico cloning confirmed effective expression of the vaccine gene in insect baculovirus vectors. CONCLUSION: This vaccine-immunoinformatics approach holds promise for the development of vaccines against Mycoplasma pneumoniae and other pathogenic non-viral and non-bacterial microbes.
Subject(s)
Bacterial Vaccines , CTLA-4 Antigen , Computational Biology , Epitopes, B-Lymphocyte , Epitopes, T-Lymphocyte , Mycoplasma pneumoniae , Pneumonia, Mycoplasma , Mycoplasma pneumoniae/immunology , Mycoplasma pneumoniae/genetics , Epitopes, T-Lymphocyte/immunology , Epitopes, T-Lymphocyte/genetics , Bacterial Vaccines/immunology , Bacterial Vaccines/genetics , Epitopes, B-Lymphocyte/immunology , Epitopes, B-Lymphocyte/genetics , Humans , Computational Biology/methods , Pneumonia, Mycoplasma/prevention & control , Pneumonia, Mycoplasma/immunology , CTLA-4 Antigen/immunology , Molecular Dynamics Simulation , Molecular Docking Simulation , Toll-Like Receptor 2/immunology , ImmunoinformaticsABSTRACT
Immune checkpoint inhibitor (ICI) therapy has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). Little is understood about the pathogenic mechanisms driving irColitis, which does not readily occur in model organisms, such as mice. To define molecular drivers of irColitis, we used single-cell multi-omics to profile approximately 300,000 cells from the colon mucosa and blood of 13 patients with cancer who developed irColitis (nine on anti-PD-1 or anti-CTLA-4 monotherapy and four on dual ICI therapy; most patients had skin or lung cancer), eight controls on ICI therapy and eight healthy controls. Patients with irColitis showed expanded mucosal Tregs, ITGAEHi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs and recirculating ITGB2Hi CD8 T cells. Cytotoxic GNLYHi CD4 T cells, recirculating ITGB2Hi CD8 T cells and endothelial cells expressing hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 therapy compared to anti-PD-1 therapy. Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption. Together, these data suggest roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and identify potential therapeutic targets for irColitis.