RESUMO
The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.
Assuntos
Cobre , Hidrogéis , Inibidores de Checkpoint Imunológico , Imunoterapia , Ativação Linfocitária , Triterpenos Pentacíclicos , Espécies Reativas de Oxigênio , Linfócitos T , Microambiente Tumoral , Triterpenos Pentacíclicos/farmacologia , Hidrogéis/química , Animais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Ativação Linfocitária/efeitos dos fármacos , Cobre/química , Microambiente Tumoral/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos Endogâmicos C57BL , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/química , Feminino , Triterpenos/farmacologia , Triterpenos/químicaRESUMO
BACKGROUND: CXC chemokine CXCL12 is involved in the pathological development of rheumatoid arthritis (RA) through abnormal migration of peripheral immune cells in the joint. Although low dose methotrexate (MTX) is clinically used to treat RA patients, CXCL12 signaling responses to MTX-mediated treatments is still not well understood. METHODS: In this study, we examined the expression of CXCR4 (cognatic receptor for CXCL12) in peripheral T cells from RA patients and arthritis mice models received from low dose MTX therapies. The effects of low dose MTX on CXCR4 were further determined via both in vitro CD3+ T cells and Cxcr4 conditional knockout (CKO) arthritis mice models. RESULTS: Our clinical data shows that low dose MTX treatment was clinically associated with down-regulated expression of chemokine receptor CXCR4 on patient peripheral T cells. In vitro, low dose MTX significantly decreased cell transmigration through down-regulated CXCR4's expression in CD3+ T cells. Consistently, CD3+ T cells treated with low dose MTX demonstrated an increased genomic hypermethylation across the promoter region of Cxcr4 gene. Furthermore, our preclinical studies showed that low dose MTX-mediated downregulation of CXCR4 significantly improved the pathological development in mouse arthritis models. Conditional disruption of the Cxcr4 gene in peripheral immune cells potentially alleviated inflammation of joints and lung tissue in the arthritis mice, though genetic modification itself overall did not change their clinical scores of arthritis, except for a significant improvement on day 45 in CXCR4 CKO arthritis mice models during the recovery phase. CONCLUSION: Our findings suggest that the effect of low dose MTX treatment could serve to eliminate inflammation in RA patients through impairment of immune cell transmigration mediated by CXCR4.
Assuntos
Antirreumáticos , Artrite Reumatoide , Regulação para Baixo , Metotrexato , Camundongos Knockout , Receptores CXCR4 , Linfócitos T , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/genética , Animais , Metotrexato/farmacologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Camundongos , Antirreumáticos/farmacologia , Masculino , Feminino , Pessoa de Meia-Idade , Movimento Celular/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/genética , Artrite Experimental/metabolismo , Artrite Experimental/patologiaRESUMO
BACKGROUND: Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer. METHODS: Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo. Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Furthermore, the efficacy of MRTX1719 in combination with immune checkpoint blockade was assessed in two syngeneic murine models with MTAP-loss tumor. RESULTS: GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces the activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors. CONCLUSION: Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.
Assuntos
Proteína-Arginina N-Metiltransferases , Purina-Núcleosídeo Fosforilase , Animais , Camundongos , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Humanos , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Purina-Núcleosídeo Fosforilase/metabolismo , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Isoquinolinas , PirimidinasRESUMO
Psoriasis is a chronic, non-contagious, immune-mediated skin disorder. Inflammation of the skin's surface is characterised by scaly white, red, or silvery spots that occur due to the hyper-proliferation of keratinocytes in the epidermal layer. Primarily, pharmaceutical drugs or immune therapy are used to treat psoriasis. We are all aware that, certain therapeutic strategies can have some adverse effects, and over time, that hidden inflammation may manifest. This article introduces a mathematical model for psoriasis, formulated by employing a set of nonlinear ordinary differential equations (ODEs) that describe the densities of T-cells, dendritic cells (DCs), keratinocytes, and mesenchymal stromal cells (MSCs) as basic cell populations. A tumor necrosis factor- α ( T N F - α ) inhibitor has been imposed from the initial stage of the treatment regime, using the optimal control theoretic approach, and the numerical results have been observed. After 80 days of monitoring using only biologic T N F - α inhibitors, if this approach did not provide the intended outcomes (when severity arises), stem cells are administered a few times in a pulsed manner as a cell replacement technique in addition to this anti T N F - α medicine. We have observed the combined therapeutic benefit of stem cell replacement with a T N F - α inhibitor from a mathematical point of view. The theoretical analysis and the numerical results revealed that stem cell transplantation, along with a T N F - α inhibitor, is a promising psoriasis treatment option moving forward.
Assuntos
Transplante de Células-Tronco Mesenquimais , Psoríase , Psoríase/terapia , Psoríase/tratamento farmacológico , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Modelos Teóricos , Queratinócitos/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Células Dendríticas/imunologiaRESUMO
Parthenolide is a germacrane sesquiterpene lactone separated from the traditional medicinal plant feverfew. Previous studies have shown that parthenolide possesses many pharmacological activities, involving anti-inflammatory and anticancer activities. However, the antitumor mechanism of parthenolide has not been fully elucidated. Thus, we investigate the potential antitumor mechanisms of parthenolactone. We predicted through network pharmacology that parthenolide may target HIF-1α to interfere with the occurrence and development of cancer. We found that parthenolide inhibited PD-L1 protein synthesis through mTOR/p70S6K/4EBP1/eIF4E and RAS/RAF/MEK/MAPK signaling pathways and promoted PD-L1 protein degradation through the lysosomal pathway, thereby inhibiting PD-L1 expression. Immunoprecipitation and Western blotting results demonstrated that parthenolide inhibited PD-L1 expression by suppressing HIF-1α and RAS cooperatively. We further proved that parthenolide inhibited cell proliferation, migration, invasion, and tube formation via down-regulating PD-L1. Moreover, parthenolide increased the effect of T cells to kill tumor cells. In vivo xenograft assays further demonstrated that parthenolide suppressed the growth of tumor xenografts. Collectively, we report for the first time that parthenolide enhanced T cell tumor-killing activity and suppressed cell proliferation, migration, invasion, and tube formation by PD-L1. The current study provides new insight for the development of parthenolide as a novel anticancer drug targeting PD-L1.
Assuntos
Antígeno B7-H1 , Proliferação de Células , Sesquiterpenos , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Humanos , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Camundongos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacosRESUMO
IL-15 is a homeostatic cytokine for human T and NK cells. However, whether other cytokines influence the effect of IL-15 is not known. We studied the impact that IL-10, TGF-ß, IL-17A, and IFN-γ have on the IL-15-induced proliferation of human T cells and the expression of HLA class I (HLA-I) molecules. Peripheral blood lymphocytes (PBLs) were labeled with CFSE and stimulated for 12 days with IL-15 in the absence or presence of the other cytokines. The proportion of proliferating T cells and the expression of cell surface HLA-I molecules were analyzed using flow cytometry. The IL-15-induced proliferation of T cells was paralleled by an increase in the expression of HC-10-reactive HLA-I molecules, namely on T cells that underwent ≥5-6 cycles of cell division. It is noteworthy that the IL-15-induced proliferation of T cells was potentiated by IL-10 and TGF-ß but not by IL-17 or IFN-γ and was associated with a decrease in the expression of HC-10-reactive molecules. The cytokines IL-10 and TGF-ß potentiate the proliferative capacity that IL-15 has on human T cells in vitro, an effect that is associated with a reduction in the amount of HC-10 reactive HLA class I molecules induced by IL-15.
Assuntos
Proliferação de Células , Antígenos de Histocompatibilidade Classe I , Interferon gama , Interleucina-10 , Interleucina-15 , Interleucina-17 , Linfócitos T , Fator de Crescimento Transformador beta , Humanos , Proliferação de Células/efeitos dos fármacos , Interferon gama/farmacologia , Interferon gama/metabolismo , Interleucina-17/farmacologia , Interleucina-17/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Interleucina-10/metabolismo , Interleucina-15/farmacologia , Interleucina-15/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/citologia , Células Cultivadas , Ativação Linfocitária/efeitos dos fármacosRESUMO
Background: Chronic spontaneous urticaria (CSU) is a highly prevalent and difficult to manage cutaneous disease characterized by the presence of recurrent urticaria, angioedema, or both, for a period of 6 weeks or longer. One of the biological treatments used for patients with CSU with an autoimmune background and bad control of the disease is omalizumab, an anti-IgE monoclonal antibody. The understanding of the mechanism of action of this biological drug in CSU along with the identification of potential biomarkers of clinical response can be helpful in the personalized management of the disease. Objective: The purpose of this study was to analyze the effect of omalizumab on peripheral blood lymphocyte subpopulations in patients with CSU in order to identify potential biomarkers of treatment response. Methods: We analyzed 71 patients with CSU [33 under omalizumab and 38 under non-immunomodulatory drugs (treated with antihistamines; NID)] and 50 healthy controls. An exhaustive immunophenotyping of whole blood T-cell subpopulations, including naïve, central memory, effector memory, effector cells, Th1, Th2, and Th17 was performed by multiparametric flow cytometry. Moreover, in CSU patients, we analyzed markers of inflammation (ESR, DD, CRP), atopy (prick test, IgE quantification), and autoimmunity (anti-thyroid antibodies and indirect basophil activation test).To evaluate the clinical activity, the Urticaria Activity Score 7 (UAS 7) test was used. Results: In patients with CSU under treatment with omalizumab, there was a significant decrease in the percentage of naïve and an increase in the percentage of central memory CD4 T cells as well as a decrease in the percentage of naïve and increase in the percentage of effector CD8 T-cell subsets. Moreover, patients under treatment with omalizumab had higher percentages of Th1 and Th2 cells than patients under treatment with NID. Conclusion: The immune monitoring of T-cell subpopulations in patients with CSU starting omalizumab, may be a useful strategy to analyze treatment response in the clinical practice.
Assuntos
Antialérgicos , Urticária Crônica , Omalizumab , Humanos , Omalizumab/uso terapêutico , Urticária Crônica/tratamento farmacológico , Urticária Crônica/imunologia , Urticária Crônica/sangue , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Antialérgicos/uso terapêutico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Idoso , Imunofenotipagem , Resultado do Tratamento , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Adulto JovemAssuntos
Doenças Autoimunes , Antígeno de Maturação de Linfócitos B , Imunossupressores , Linfócitos T , Humanos , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Antígeno de Maturação de Linfócitos B/imunologia , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Anticorpos Biespecíficos/administração & dosagem , Feminino , Adulto , Pessoa de Meia-Idade , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Resultado do TratamentoRESUMO
This mini-review reports a brief description of the first experiments conducted by Canti's group on the role of photodynamic therapy in generating immunity against cancer. It highlights for the first time the effective role of PDT in the induction of anti-tumor T lymphocytes and shows that this effect is tumor-specific. It has also been reported how this adoptive immunity can improve the efficacy of chemotherapy. These studies have helped to open an important new field of scientific research on the role of PDT-generated immunity and to stimulate today's important new pre-clinical approaches.
Assuntos
Neoplasias , Fotoquimioterapia , Fármacos Fotossensibilizantes , Humanos , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacosRESUMO
This paper describes the synthesis, characterization, and functional activity of 26 MegaMolecule-based bispecific antibody mimics for T-cell redirection toward HER2+ cancer cells. The work reports functional bispecific MegaMolecules that bind both receptor targets, and recruit and activate T-cells resulting in lysis of the target tumor cells. Changing the orientation of linkage between Fabs against either HER2 or CD3ε results in an approximately 150-fold range in potency. Increasing scaffold valency from Fab dimers up to tetramers improves the potency of the antibody mimics up to 5-fold, but with diminishing returns in effective dose beyond trimeric formats. Antibody mimics that present either one or two Fabs against either receptor target allows for initial engagement of one cell type over the other. Finally, the antibody mimics significantly reduce HER2+ tumor volumes in a humanized xenograft model of breast cancer.
Assuntos
Anticorpos Biespecíficos , Receptor ErbB-2 , Linfócitos T , Humanos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/imunologia , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Animais , Camundongos , Complexo CD3/imunologia , Linhagem Celular Tumoral , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/imunologiaRESUMO
Several FDA-approved adjuvants signal through the NLRP3 inflammasome and IL-1ß release. Identifying small molecules that induce IL-1ß release could allow targeted delivery and structure-function optimization, thereby improving safety and efficacy of next-generation adjuvants. In this work, we leverage our existing high throughput data set to identify small molecules that induce IL-1ß release. We find that ribociclib induces IL-1ß release when coadministered with a TLR4 agonist in an NLRP3- and caspase-dependent fashion. Ribociclib was formulated with a TLR4 agonist into liposomes, which were used as an adjuvant in an ovalbumin prophylactic vaccine model. The liposomes induced antigen-specific immunity in an IL-1 receptor-dependent fashion. Furthermore, the liposomes were coadministered with a tumor antigen and used in a therapeutic cancer vaccine, where they facilitated rejection of E.G7-OVA tumors. While further chemical optimization of the ribociclib scaffold is needed, this study provides proof-of-concept for its use as an IL-1 producing adjuvant in various immunotherapeutic contexts.
Assuntos
Quinase 4 Dependente de Ciclina , Inflamassomos , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR , Purinas , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-1beta/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Animais , Humanos , Camundongos , Purinas/farmacologia , Purinas/química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T/imunologia , Camundongos Endogâmicos C57BL , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Lipossomos/química , Vacinas Anticâncer/farmacologia , Vacinas Anticâncer/imunologia , Feminino , AminopiridinasRESUMO
Oxaliplatin is currently used for chemotherapy in patients with hepatocellular carcinoma, but its increasing tolerance to tumours over time limits its clinical application. Studies have shown that high PD-L1 expression promotes the polarization of M2 macrophages. The increased infiltration of M2 macrophages, including those in HCC, is positively correlated with poor prognosis in various solid tumours. We found that oxaliplatin promoted the expression of PD-L1 in liver cancer cells, which might be attributed partly to the tolerance of tumours to oxaliplatin. Therefore, in this study, we explored the antitumour effect of attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin via Western blotting, immunohistochemistry, immunofluorescence, and flow cytometry. The results revealed that attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin more significantly inhibited tumour growth in tumour-bearing mice, suppressed the expression of PD-L1 in tumour tissue, increased the apoptosis of tumour cells and the expression of the tumour-related protein cleaved-caspase3, and increased the infiltration of M1 macrophages and T lymphocytes in tumour tissues. Moreover, the combination therapy increased the activation of T cells and the number of T lymphocytes and NK cells in the spleens of the mice and improved the overall antitumour immune response in the mice. Our results confirmed that attenuated Salmonella harbouring siRNA-PD-L1 combined with oxaliplatin had a significant antitumour effect and did not increase the incidence of toxic side effects, providing a theoretical reference for addressing oxaliplatin tolerance in the treatment of hepatocellular carcinoma.
Assuntos
Antígeno B7-H1 , Carcinoma Hepatocelular , Neoplasias Hepáticas , Oxaliplatina , RNA Interferente Pequeno , Animais , Oxaliplatina/uso terapêutico , Oxaliplatina/farmacologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/antagonistas & inibidores , RNA Interferente Pequeno/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Camundongos , Humanos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Salmonella , Camundongos Endogâmicos BALB C , Masculino , Terapia Combinada , Modelos Animais de Doenças , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacosRESUMO
Tropomyosin was reported as an important allergen in Crassostrea angulata and designated as Cra a 1. The localization of the T cell epitopes and the reduction of the immunoreactivity of Cra a 1 are still lacking. In this study, four T cell epitopes were identified by using wild-type Cra a 1 (wtCra a 1)-immunized mouse splenocytes cultured with synthetic peptides. The immunoreactivity was maintained after chemical denaturation treatment, indicating that the linear epitope is an immunodominant epitope of wtCra a 1. Furthermore, the hypoallergenic derivative (mCra a 1) was developed by the deletion of linear B cell epitopes and retention of T cell epitopes. mCra a 1 could stimulate CD4+T cell proliferation and upregulate interleukin-10 secretion. Overall, basophil activation by mCra a 1 was low, but its ability to induce T cell proliferation was retained, suggesting that mCra a 1 may serve as a viable candidate for treating oyster allergy.
Assuntos
Alérgenos , Crassostrea , Epitopos de Linfócito B , Epitopos de Linfócito T , Animais , Camundongos , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Alérgenos/imunologia , Alérgenos/química , Alérgenos/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/genética , Crassostrea/imunologia , Crassostrea/química , Crassostrea/genética , Tropomiosina/imunologia , Tropomiosina/genética , Tropomiosina/química , Camundongos Endogâmicos BALB C , Feminino , Humanos , Proliferação de Células/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Hipersensibilidade a Frutos do Mar/imunologia , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacosRESUMO
Niacin was found in the lysolecithin model of multiple sclerosis (MS) to promote the phagocytic clearance of debris and enhance remyelination. Lysolecithin lesions have prominent microglia/macrophages but lack lymphocytes that populate plaques of MS or its experimental autoimmune encephalomyelitis (EAE) model. Thus, the current study assessed the efficacy of niacin in EAE. We found that niacin inconsistently affects EAE clinical score, and largely does not ameliorate neuropathology. In culture, niacin enhances phagocytosis by macrophages, but does not reduce T cell proliferation. We suggest that studies of niacin for potential remyelination in MS should include a therapeutic that targets adaptive immunity.
Assuntos
Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Esclerose Múltipla , Niacina , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Animais , Niacina/uso terapêutico , Feminino , Camundongos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Fagocitose/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Células Cultivadas , Modelos Animais de Doenças , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Tumor-associated macrophages (TAMs) and other myelomonocytic cells are implicated in regulating responsiveness to immunotherapies, including immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis. We have developed an ex vivo high-throughput approach to discover modulators of macrophage-mediated T cell suppression, which can improve clinical outcomes of ICIs. We screened 1,430 Food and Drug Administration (FDA)-approved small-molecule drugs using a co-culture assay employing bone-marrow-derived macrophages (BMDMs) and splenic-derived T cells. This identified 57 compounds that disrupted macrophage-mediated T cell suppression. Seven compounds exerted prominent synergistic T cell expansion activity when combined with αPD-L1. These include four COX1/2 inhibitors and two myeloid cell signaling inhibitors. We demonstrate that the use of cyclooxygenase (COX)1/2 inhibitors in combination with αPD-L1 decreases tumor growth kinetics and enhances overall survival in triple-negative breast cancer (TNBC) tumor models in a CD8+ T cell-dependent manner. Altogether, we present a rationalized approach for identifying compounds that synergize with ICI to potentially enhance therapeutic outcomes for patients with solid tumors.
Assuntos
Antígeno B7-H1 , Macrófagos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Animais , Humanos , Camundongos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Feminino , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Imunoterapia/métodos , Inibidores de Ciclo-Oxigenase/farmacologiaRESUMO
INTRODUCTION: T-cell redirecting bispecific antibodies (BsAbs), targeting B-cell maturation antigen (BCMA) or G-protein - coupled receptor class C group 5 member D (GPRC5D), are efficacious new agents for the treatment of patients with relapsed or refractory MM. AREAS COVERED: This review discusses the pharmacokinetic properties, efficacy, and safety profile of T-cell redirecting BsAbs in MM, with a special focus on their optimal dosing schedule, resistance mechanisms and future strategies to enhance efficacy, reduce toxicity, and maximize duration of response. EXPERT OPINION: To further improve the efficacy of BsAbs, ongoing studies are investigating whether combination therapy can enhance depth and duration of response. An important open question is also to what extent response to BsAbs can be improved when these agents are used in earlier lines of therapy. In addition, more evidence is needed on rational de-intensification strategies of BsAb dosing upon achieving a sufficient response, and if (temporary) treatment cessation is possible in patients who have achieved a deep remission (e.g. complete response or minimal residual disease-negative status).
Assuntos
Anticorpos Biespecíficos , Mieloma Múltiplo , Linfócitos T , Humanos , Anticorpos Biespecíficos/farmacocinética , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/imunologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Animais , Antígeno de Maturação de Linfócitos B/imunologia , Antígeno de Maturação de Linfócitos B/antagonistas & inibidoresRESUMO
CD99 is a transmembrane protein overexpressed in Acute Myeloid Leukemia (AML), presenting a potential novel therapeutic target. Our group has previously developed anti-CD99-A192 (α-CD99-A192), comprising of single chain variable fragment (scFv) and elastin-like polypeptides (ELPs), and reported promising anti-leukemic activity in AML preclinical models. Treatment with α-CD99-A192 induced apoptosis in AML cell lines and prolonged survival in AML xenograft models. Considering CD99's expression and role in T cell activation, in the current study, we propose that α-CD99-A192 plays a dual function, i.e., targeting leukemic cells and activating T cells. This manuscript reports the effects of α-CD99-A192 on T cells in the context of AML. α-CD99-A192 treatment enhances T cell proliferation and activation and increases the release of pro-inflammatory cytokines along with increased aggregation of T cells, which culminates in heightened cytotoxicity against leukemic cells. Altogether, these findings suggest α-CD99-A192 enhances T cell activation and cytotoxic potential consistent with dual mechanisms of action for α-CD99-A192.
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Antígeno 12E7 , Leucemia Mieloide Aguda , Ativação Linfocitária , Nanopartículas , Linfócitos T , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Antígeno 12E7/metabolismo , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Animais , Anticorpos de Cadeia Única/farmacologia , Citocinas/metabolismo , Apoptose/efeitos dos fármacosRESUMO
For adoptive therapy with T cell receptor engineered T (TCR-T) cells, the quantity and quality of the final cell product directly affect their anti-tumor efficacy. The post-transfer efficacy window of TCR-T cells is keen to optimizing attempts during the manufacturing process. Cbl-b is a E3 ubiquitin ligase previously shown with critical negative impact in T cell functions. This study investigated whether strategic inclusion of a commercially available small inhibitor targeting Cbl-b (Cbl-b-IN-1) prior to T cell activation could enhance the quality of the final TCR-T cell product. Examination with both PBMCs and TCR-T cells revealed that Cbl-b-IN-1 treatment promoted TCR expression efficiency, T cell proliferation potential and, specifically, cell survival capability post antigenic stimulation. Cbl-b-IN-1 exposure facilitated T cells in maintaining less differentiated states with enhanced cytokine production. Further, we found that Cbl-b-IN-1 effectively augmented the activation of TCR signaling, shown by increased phosphorylation levels of Zeta-chain-associated protein kinase 70 (ZAP70) and phospholipase c-γ1 (PLCγ1). In conclusion, our results evidence that the inclusion of Cbl-b inhibitor immediately prior to TCR-T cell activation may enhance their proliferation, survival, and function potentials, presenting an applicable optimization strategy for immunotherapy with adoptive cell transfer.
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Proteínas Adaptadoras de Transdução de Sinal , Diferenciação Celular , Proliferação de Células , Citocinas , Ativação Linfocitária , Proteínas Proto-Oncogênicas c-cbl , Receptores de Antígenos de Linfócitos T , Transdução de Sinais , Linfócitos T , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Citocinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fosfolipase C gama/metabolismo , Proteína-Tirosina Quinase ZAP-70/metabolismo , Fosforilação/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Fenótipo , Sobrevivência Celular/efeitos dos fármacosRESUMO
Alterations to the gut microbiota are associated with ulcerative colitis (UC), whereas restoration of normobiosis can effectively alleviate UC. l-Theanine has been shown to reshape the gut microbiota and regulate gut immunity. To investigate the mechanisms by which l-theanine alleviates UC, we used l-theanine and l-theanine fecal microbiota solution to treat UC mice. In this study, we used l-theanine and l-theanine fecal microbiota solution to treat UC mice to explore the mechanism by which l-theanine alleviates UC. By reducing inflammation in the colon, we demonstrated that l-theanine alleviates symptoms of UC. Meanwhile, l-theanine can improve the abundance of microbiota related to short-chain fatty acid, bile acid, and tryptophan production. Single-cell sequencing results indicated that l-theanine-mediated suppression of UC was associated with immune cell changes, especially regarding macrophages and T and B cells, and validated the immune cell responses to the gut microbiota. Further, flow cytometry results showed that the ability of dendritic cells, macrophages, and monocytes to present microbiota antigens to colonic T cells in an MHC-II-dependent manner was reduced after treating normal mouse fecal donors with l-theanine. These results demonstrate that l-theanine modulates colon adaptive and innate immunity by regulating the gut microbiota in an MHC-II-dependent manner, thereby alleviating UC.