RESUMO
Combination immunotherapy improves outcomes in metastatic melanoma, but the underlying mechanisms remain unclear. In this issue of Cancer Cell, Wang et al.1 report dynamics and transcriptional states of CD8+ T cell clones over time in patients treated with anti-PD-1, anti-CTLA-4, or a combination of the two. These findings have important implications for understanding and monitoring combination immunotherapy.
Assuntos
Linfócitos T CD8-Positivos , Imunoterapia , Melanoma , Humanos , Imunoterapia/métodos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Melanoma/imunologia , Melanoma/terapia , Melanoma/tratamento farmacológico , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaRESUMO
This study investigates the effects of Daphnes Cortex and its processed products on the differentiation of Th17/Treg cells in SD rats with type â ¡ collagen-induced arthritis(CIA).Sixty-four SD rats were randomly divided into the normal group(normal),model group(model),fried Daphne giraldii Nitsche low-dose and high-dose groups(FDGN-L group, FDGN-H group),raw D. giraldii Nitsche low-dose and high-dose groups(RDGN-L group, RDGN-H group),daphnetin group(DAPH group),and tripterygium glycosides group(GTW group).Except for the normal group, the CIA model was immunized on the seventh day after the first immunization, and was gavaged for 28 days after the second immunization.After sampling, the inflammation of articular synovial membrane in CIA rats was observed by hematoxylin-eosin(HE)staining; the levels of transforming growth factor-ß(TGF-ß),interferon-γ(IFN-γ),interleukin(IL)-2,IL-4,and IL-10 in serum were detected by enzyme-linked immunosorbent assay(ELISA); real-time reverse transcription-PCR(qRT-PCR)and Western blot were used to detect the mRNA and protein expressions of cluster of differentiation(CD) 80(B7-1),CD 86(B7-2),CD28,and cytotoxic T lymphocyte-associated antigen 4(CTLA-4)in the synovial membrane of rats; flow cytometry was used to detect the proportion of Th17 and Treg cells in the synovial membrane of rats.The results showed that compared with the normal group, the joint synovial inflammation of rats in the model group was significantly aggravated, the arthritis index was significantly increased, and the immune organ index was increased(P<0.01).Compared with the model group, each drug administration group could improve the joint inflammation of rats to varying degrees, reduce the arthritis index, inhibit synovial hyperplasia, and reduce the immune organ index; compared with the model group, the serum levels of IL-2 and IFN-γ in each drug administration group were significantly decreased(P<0.01),TGF-ß,IL-4,and IL-10 were significantly increased(P<0.01),the mRNA and protein expressions of B7-1 and CTLA-4 in the synovial membrane were significantly increased(P<0.01),and the proportion of Th17 cells and Treg cells in the joint tissue was significantly decreased(P<0.01).In conclusion, Daphnes Cortex inhibits the expression of Th17 cells in CIA rats and promotes the expression of Treg cells by regulating the B7/CD28/CTLA-4 pathway and the balance of Th17/Treg, thereby treating rheumatoid arthritis.
Assuntos
Artrite Experimental , Antígenos CD28 , Antígeno CTLA-4 , Daphne , Ratos Sprague-Dawley , Animais , Ratos , Artrite Experimental/imunologia , Artrite Experimental/tratamento farmacológico , Masculino , Daphne/química , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/genética , Antígenos CD28/imunologia , Antígenos CD28/genética , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Células Th17/imunologia , Células Th17/efeitos dos fármacos , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Antígeno B7-1/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Humanos , Transdução de Sinais/efeitos dos fármacosRESUMO
Targeting checkpoints for immune cell activation has been acknowledged known as one of the most effective way to activate anti-tumor immune responses. Among them, drugs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for clinical treatment though several more are in advanced stages of development, which demonstrated durable response rates and manageable safety profile. However, its therapy efficacy is unsatisfactory in pancreatic cancer (PC), which can be limited by the overall condition of patients, the pathological type of PC, the expression level of tumor related genes, etc. To improve clinical efficiency, various researches have been conducted, and the efficacy of combination therapy showed significantly improvement compared to monotherapy. This review analyzed current strategies based on anti-CTLA-4 combination immunotherapy, providing totally new idea for future research.
Assuntos
Antígeno CTLA-4 , Inibidores de Checkpoint Imunológico , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Animais , Imunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Brucellosis is a zoonotic disease caused by Brucella, which is difficult to eliminate by conventional drugs. Therefore, a novel multi-epitope vaccine (MEV) was designed to prevent human Brucella infection. Based on the method of "reverse vaccinology", cytotoxic T lymphocyte epitopes (CTLEs), helper T lymphocyte epitopes (HTLEs), linear B-cell epitopes (LBEs) and conformational B-cell epitopes (CBEs) of four Brucella proteins (VirB9, VirB10, Omp 19 and Omp 25) were obtained. In order to keep the correct protein folding, the multiple epitopes was constructed by connecting epitopes through linkers. In view of the significant connection between human leukocyte antigen CTLA-4 and B7 molecules found on antigen presenting cells (APCs), a new vaccine (V_C4MEV) for preventing brucellosis was created by combining CTLA-4 immunoglobulin variable region (IgV_CTLA-4) with MEV protein. Immunoinformatics analysis showed that V_C4MEV has a good secondary and tertiary structure. Additionally, molecular docking and molecular dynamics simulation (MD) revealed a robust binding affinity between IgV_ CTLA-4 and the B7 molecule. Notably, the vaccine V_C4MEV was demonstrated favorable immunogenicity and antigenicity in both in vitro and in vivo experiments. V_C4MEV had the potential to activate defensive cells and immune responses, offering a hopeful approach for developing vaccines against Brucella in the upcoming years.
Assuntos
Vacina contra Brucelose , Brucella , Brucelose , Antígeno CTLA-4 , Biologia Computacional , Epitopos de Linfócito B , Epitopos de Linfócito T , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Brucelose/prevenção & controle , Brucelose/imunologia , Epitopos de Linfócito B/imunologia , Antígeno CTLA-4/imunologia , Epitopos de Linfócito T/imunologia , Vacina contra Brucelose/imunologia , Animais , Humanos , Brucella/imunologia , Brucella/genética , Camundongos , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/química , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas da Membrana Bacteriana Externa/genética , Imunoinformática , LipoproteínasRESUMO
Infections caused by the influenza virus lead to both epidemic and pandemic outbreaks in humans and animals. Owing to their rapid production, safety, and stability, DNA vaccines represent a promising avenue for eliciting immunity and thwarting viral infections. While DNA vaccines have demonstrated substantial efficacy in murine models, their effectiveness in larger animals remains subdued. This limitation may be addressed by augmenting the immunogenicity of DNA-based vaccines. In the investigation here, protein expression was enhanced via codon optimization and then mouse cytotoxic T-lymphocyte antigen 4 (CTLA-4) was harnessed as a modulatory adjunct to bind directly to antigen-presenting cells. Further, the study evaluated the immunogenicity of two variants of the hemagglutinin (HA) antigen, i.e. the full-length and the C-terminal deletion versions. The study findings revealed that the codon-optimized HA gene (pcHA) led to increased protein synthesis, as evidenced by elevated mRNA levels. Codon optimization also significantly bolstered both cellular and humoral immune responses. In cytokine assays, all plasmid constructs, particularly pCTLA4-cHA, induced robust interferon (IFN)-γ production, while interleukin (IL)-4 levels remained uniformly non-significant. Mice immunized with pcHA displayed an augmented presence of IFNγ+ T-cells, underscoring the enhanced potency of the codon-optimized HA vaccine. Contrarily, CTLA-4-fused DNA vaccines did not significantly amplify the immune response.
Assuntos
Antígeno CTLA-4 , Códon , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vacinas contra Influenza , Infecções por Orthomyxoviridae , Vacinas de DNA , Animais , Vacinas de DNA/imunologia , Vacinas de DNA/genética , Camundongos , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Códon/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Humanos , Feminino , Camundongos Endogâmicos BALB C , Modelos Animais de Doenças , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Vírus da Influenza A Subtipo H1N1/imunologiaRESUMO
Electronic cigarettes (e-cigarettes) are thought to pose low risk of cancer because the components of e-cigarette liquid are not carcinogens. We analyzed the effects of the two major components, PG/VG and nicotine, on tumor development in preclinical models. We found that PG/VG promoted tumor cell migration in migration assays and contributed to more aggressive, metastatic, and immunosuppressive tumors in vivo, aggravated by the presence of nicotine. Whole body exposure of mice to PG/VG and nicotine rendered animals more susceptible to developing tumors with high frequencies of infiltrating proinflammatory macrophages expressing IL-6 and TNFα. Moreover, tumor-infiltrating and circulating T cells in e-cigarette exposed mice showed increased levels of immune checkpoints including CTLA4 and PD-1. Treatment with anti-CTLA4 antibody was able to abrogate metastasis with no detrimental effects on its ability to induce tumor regression in exposed mice. These findings suggest that the major components used in e-cigarette fluid can impact tumor development through induced immunosuppression.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Nicotina , Animais , Camundongos , Metástase Neoplásica , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Antígeno CTLA-4/imunologia , Feminino , Movimento Celular/efeitos dos fármacos , Receptor de Morte Celular Programada 1RESUMO
Tumor immunotherapy has garnered considerable attention, emerging as a new standard of care in cancer treatment. The conventional targets, such as VEGF and EGFR, have been extended to others including BRAF and PD-1/PD-L1, which have shown significant potential in recent cancer treatments. This review aims to succinctly overview the impact and mechanisms of therapies that modulate PD-1/PD-L1 expression by targeting VEGF, EGFR, LAG-3, CTLA-4 and BRAF. We investigated how modulation of PD-1/PD-L1 expression impacts growth factor signaling, shedding light on the interplay between immunomodulatory pathways and growth factor networks within the tumor microenvironment. By elucidating these interactions, we aim to provide insights into novel potential synergistic therapeutic strategies for cancer immunotherapy.
Assuntos
Antígeno B7-H1 , Imunoterapia , Neoplasias , Receptor de Morte Celular Programada 1 , Transdução de Sinais , Microambiente Tumoral , Humanos , Antígeno B7-H1/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Animais , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptores ErbB/imunologia , Proteínas Proto-Oncogênicas B-raf , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/antagonistas & inibidoresRESUMO
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.
Assuntos
Anticorpos Biespecíficos , Linfócitos T CD8-Positivos , Antígeno CTLA-4 , Linfócitos T Reguladores , Animais , Camundongos , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/uso terapêutico , Humanos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptores CCR8/imunologia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Transdução de Sinais/efeitos dos fármacos , Feminino , Ensaios Antitumorais Modelo de Xenoenxerto , Macaca fascicularisRESUMO
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.
Assuntos
Antígeno B7-H1 , Antígeno CTLA-4 , Inibidores de Checkpoint Imunológico , Neoplasias , Receptor de Morte Celular Programada 1 , Humanos , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Animais , Resultado do TratamentoRESUMO
Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8+ T cells and exhausted CD8+ T cell (TEX) clones. Focused analyses of TEX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor TEX, which synergizes with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.
Assuntos
Linfócitos T CD8-Positivos , Antígeno CTLA-4 , Inibidores de Checkpoint Imunológico , Melanoma , Receptor de Morte Celular Programada 1 , Humanos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Feminino , Análise de Célula Única/métodos , MasculinoRESUMO
DENV infection outcomes depend on the host's variable expression of immune receptors and mediators, leading to either resolution or exacerbation. While the NS3 protein is known to induce robust immune responses, the specific impact of its protease region epitopes remains unclear. This study investigated the effect of recombinant NS3 protease region proteins from all four DENV serotypes on splenocyte activation in BALB/c mice (n = 5/group). Mice were immunized with each protein, and their splenocytes were subsequently stimulated with homologous antigens. We measured the expression of costimulatory molecules (CD28, CD80, CD86, CD152) by flow cytometry, along with IL-2 production, CD25 expression, and examined the antigen-specific activation of CD4 + and CD8 + T cells. Additionally, the expression of IL-1, IL-10, and TGF-ß1 in splenocytes from immunized animals was assessed. Apoptosis was evaluated using Annexin V/PI staining and DNA fragmentation analysis. Stimulation of splenocytes from immunized mice triggered apoptosis (phosphatidylserine exposure and caspase 3/7 activation) and increased costimulatory molecule expression, particularly CD152. Low IL-2 production and low CD25 expression, as well as sustained expression of the IL-10 gene. These results suggest that these molecules might be involved in mechanisms by which the NS3 protein contributes to viral persistence and disease pathogenesis.
Assuntos
Apoptose , Antígeno CTLA-4 , Vírus da Dengue , Camundongos Endogâmicos BALB C , Baço , Proteínas não Estruturais Virais , Animais , Camundongos , Baço/imunologia , Baço/virologia , Vírus da Dengue/imunologia , Vírus da Dengue/genética , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Proteínas não Estruturais Virais/imunologia , Proteínas não Estruturais Virais/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/genética , Imunização , Dengue/imunologia , Dengue/virologia , Citocinas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologiaRESUMO
The risk for suffering immune checkpoint inhibitors (ICIs)-associated myocarditis increases in patients with pre-existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single-cell RNA sequencing, and flow cytometry are used to decipher how anti-cytotoxic T lymphocyte antigen-4 m2a antibody (anti-CTLA-4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti-CTLA-4 m2a antibody increases cardiac fibroblast-derived C-X-C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1-Cxcr2 chemotaxis. It is identified that the C-C motif chemokine ligand 5 (Ccl5)-neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF-κB signaling, and cellular response to interferon-gamma and that the Ccl5-neutrophil subpopulation and its-associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti-CTLA-4 m2a antibody-induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5-neutrophil subpopulation plays a critical role in aggravating anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs-associated myocarditis.
Assuntos
Doenças Autoimunes , Quimiocina CCL5 , Miocardite , Animais , Masculino , Camundongos , Doenças Autoimunes/imunologia , Quimiocina CCL5/imunologia , Quimiocina CCL5/metabolismo , Quimiocina CCL5/genética , Antígeno CTLA-4/imunologia , Modelos Animais de Doenças , Traumatismos Cardíacos/imunologia , Traumatismos Cardíacos/induzido quimicamente , Miocardite/imunologia , Infiltração de Neutrófilos/efeitos dos fármacosRESUMO
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.
Assuntos
Neoplasias da Mama , Antígeno CTLA-4 , Humanos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Feminino , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Anticorpos Monoclonais/uso terapêutico , Linfócitos T Reguladores/imunologia , Linfócitos do Interstício Tumoral/imunologiaRESUMO
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.
Assuntos
Imunoterapia , Animais , Camundongos , Imunoterapia/métodos , Linhagem Celular Tumoral , Feminino , Terapia Combinada , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia , Interleucina-12 , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Radioimunoterapia/métodos , Interleucina-2 , Camundongos Endogâmicos BALB C , Memória Imunológica , Estadiamento de Neoplasias , Neoplasias do Colo/terapia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologiaRESUMO
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.
Assuntos
Receptor Celular 2 do Vírus da Hepatite A , Animais , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Camundongos , Transplante de Células-Tronco Hematopoéticas , Efeito Enxerto vs Leucemia/imunologia , Efeito Enxerto vs Leucemia/genética , Humanos , Aloenxertos , Ligantes , Oncogenes , Linfócitos T CD8-Positivos/imunologia , Camundongos Knockout , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Regulação Leucêmica da Expressão GênicaRESUMO
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.
Assuntos
Antígeno B7-H1 , Carcinoma de Células Escamosas , Plasticidade Celular , Transição Epitelial-Mesenquimal , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias Cutâneas , Animais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Camundongos , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Imunoterapia/métodos , Transição Epitelial-Mesenquimal/imunologia , Plasticidade Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/imunologia , Receptores Virais/metabolismo , Receptores Virais/genética , Antígeno B7-1/metabolismo , Receptores Imunológicos/metabolismoRESUMO
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.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Inibidores de Checkpoint Imunológico , Imunoterapia , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/imunologia , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/imunologia , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Microambiente Tumoral/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Terapia Combinada , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , AnimaisRESUMO
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.
Assuntos
Antígeno CTLA-4 , Receptor Celular 2 do Vírus da Hepatite A , Imuno-Histoquímica , Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/imunologia , Meningioma/patologia , Meningioma/metabolismo , Masculino , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/metabolismo , Feminino , Pessoa de Meia-Idade , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Idoso , Adulto , Biomarcadores Tumorais/metabolismo , Proteínas de Checkpoint Imunológico/metabolismo , Idoso de 80 Anos ou mais , Adulto Jovem , AdolescenteRESUMO
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.