RESUMO
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. IL1 receptor type 2 (IL1R2) promotes breast tumor-initiating cell (BTIC) self-renewal and tumor growth in TNBC, indicating that targeting it could improve patient treatment. In this study, we observed that IL1R2 blockade strongly attenuated macrophage recruitment and the polarization of tumor-associated macrophages (TAM) to inhibit BTIC self-renewal and CD8+ T-cell exhaustion, which resulted in reduced tumor burden and prolonged survival in TNBC mouse models. IL1R2 activation by TAM-derived IL1ß increased PD-L1 expression by interacting with the transcription factor Yin Yang 1 (YY1) and inducing YY1 ubiquitination and proteasomal degradation in both TAMs and TNBC cells. Loss of YY1 alleviated the transcriptional repression of c-Fos, which is a transcriptional activator of PDL-1. Combined treatment with an IL1R2-neutralizing antibodies and anti-PD-1 led to enhanced antitumor efficacy and reduced TAMs, BTICs, and exhausted CD8+ T cells. These results suggest that IL1R2 blockade might be a strategy to potentiate immune checkpoint blockade efficacy in TNBC to improve patient outcomes. Significance: IL1R2 in both macrophages and breast cancer cells orchestrates an immunosuppressive tumor microenvironment by upregulating PD-L1 expression and can be targeted to enhance the efficacy of anti-PD-1 in triple-negative breast cancer.
Assuntos
Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Camundongos , Humanos , Feminino , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos dos fármacos , Linhagem Celular Tumoral , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Fator de Transcrição YY1/metabolismo , Fator de Transcrição YY1/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacosRESUMO
BACKGROUND: Previous studies have substantiated that M2-activated tumor-associated macrophages (M2-TAMs) are involved in multiple malignancies. Presently, we probe the impact and related mechanisms of 13-methyl-palmatrubine (13MP), the Corydalis yanhusuo extract, on M2-TAM-mediated non-small cell lung cancer (NSCLC) development. METHODS: IL-4 and IL-13 were adopted to induce M2-TAMs. The polarization state of TAMs was evaluated by quantitative reverse transcription PCR (qRT-PCR), Western blot (WB) and cellular immunofluorescence. NSCLC cells (A549 and NCL-H1975) were co-cultured with the conditioned medium (CM) of M2-TAMs. Followed by 13MP treatment, cell viability, proliferation, invasion, epithelial-mesenchymal transition (EMT), and in-vivo growth of NSCLC cells were determined. Additionally, human umbilical vein endothelial cells (HUVECs) were co-cultured with the CM of M2-TAMs. The tube formation assay was made to test the tube formation capacity of HUVECs, and the expression of MMP3, MMP9, and VEGF was assessed by WB in the co-culture model. Mechanistically, WB was performed to validate the expression of the PI3K/AKT and JAK/STAT3 pathways in NSCLC cells (A549 and NCL-H1975) as well as in endothelial cell lines co-cultured with M2-TAMs. RESULTS: 13MP inhibited the proliferation, invasion, EMT, growth and enhanced apoptosis of NSCLC cells. 13MP dose-dependently boosted the polarization of TAM from M2 to M1 state. M2-TAMs enhanced the malignant behaviors of NSCLC cells, whereas 13MP hindered M2-TAM-mediated NSCLC cell proliferation and invasion. Meanwhile, 13MP weakened the M2-TAM-mediated angiogenesis. Moreover, 13MP inactivated the PI3K/AKT and JAK/STAT3 signaling in A549 cells, NCL-H1975 cells and HUVECs. CONCLUSION: 13MP suppresses TAM-mediated NSCLC progression via transforming the polarization of TAM from M2 to M1.
Assuntos
Antineoplásicos/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Alcaloides de Berberina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Citocinas/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologiaRESUMO
During the last decade, we have persistently addressed the question, "how can the innate immune system be used as a therapeutic tool to eliminate cancer?" A cancerous tumor harbors innate immune cells such as macrophages, which are held in the tumor-promoting M2 state by tumor-cell-released cytokines. We have discovered that these tumor-associated macrophages (TAM) are repolarized into the nitric oxide (NO)-generating tumoricidal M1 state by the dietary agent curcumin (CC), which also causes recruitment of activated natural killer (NK) cells and cytotoxic T (Tc) cells into the tumor, thereby eliminating cancer cells as well as cancer stem cells. Indications are that this process may be NO-dependent. Intriguingly, the maximum blood concentration of CC in mice never exceeds nanomolar levels. Thus, our results submit that even low, transient levels of curcumin in vivo are enough to cause repolarization of the TAM and recruitment NK cells as well as Tc cells to eliminate the tumor. We have observed this phenomenon in two cancer models, glioblastoma and cervical cancer. Therefore, this approach may yield a general strategy to fight cancer. Our mechanistic studies have so far implicated induction of STAT-1 in this M2âM1 switch, but further studies are needed to understand the involvement of other factors such as the lipid metabolites resolvins in the CC-evoked anticancer pathways.
Assuntos
Curcumina/uso terapêutico , Glioblastoma/tratamento farmacológico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Feminino , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Camundongos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Óxido Nítrico/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologiaRESUMO
Within the prostate tumor microenvironment (TME) there are complex multi-faceted and dynamic communication occurring between cancer cells and immune cells. Macrophages are key cells which infiltrate and surround tumor cells and are recognized to significantly contribute to tumor resistance and metastases. Our understanding of their function in the TME is commonly based on in vitro and in vivo models, with limited research to confirm these model observations in human prostates. Macrophage infiltration was evaluated within the TME of human prostates after 72 h culture of fresh biopsies samples in the presence of control or enzalutamide. In addition to immunohistochemistry, an optimized protocol for multi-parametric evaluation of cellular surface markers was developed using flow cytometry. Flow cytometry parameters were compared to clinicopathological features. Immunohistochemistry staining for 19 patients with paired samples suggested enzalutamide increased the expression of CD163 relative to CD68 staining. Techniques to validate these results using flow cytometry of dissociated biopsies after 72 h of culture are described. In a second cohort of patients with Gleason grade group ≥ 3 prostate cancer, global macrophage expression of CD163 was unchanged with enzalutamide treatment. However, exploratory analyses of our results using multi-parametric flow cytometry for multiple immunosuppressive macrophage markers suggest subgroup changes as well as novel associations between circulating biomarkers like the neutrophil to lymphocyte ratio (NLR) and immune cell phenotype composition in the prostate TME. Further, we observed an association between B7-H3 expressing tumor-associated macrophages and the presence of intraductal carcinoma. The use of flow cytometry to evaluate ex vivo cultured prostate biopsies fills an important gap in our ability to understand the immune cell composition of the prostate TME. Our results highlight novel associations for further investigation.
Assuntos
Antagonistas de Androgênios/farmacologia , Benzamidas/farmacologia , Biomarcadores Tumorais/análise , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Neoplasias da Próstata/terapia , Macrófagos Associados a Tumor/efeitos dos fármacos , Idoso , Antagonistas de Androgênios/uso terapêutico , Benzamidas/uso terapêutico , Células Cultivadas , Quimioterapia Adjuvante/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Cultura Primária de Células , Próstata/citologia , Próstata/efeitos dos fármacos , Próstata/imunologia , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologiaRESUMO
Although the main focus of immuno-oncology has been manipulating the adaptive immune system, tumor associated macrophages (TAMs) are the main infiltrating component in the tumor microenvironment (TME) and play a critical role in cancer progression. TAMs are mainly divided into two different subtypes: macrophages with antitumor or killing activity are called M1 while tumor-promoting or healing macrophages are named M2. Therefore, controlling the polarization of TAMs is an important strategy for cancer treatment, but there is no particularly effective means to regulate the polarization process. Here, combined systems pharmacology targets and pathways analysis strategy, we uncovered Scutellariae Radix (SR) has the potential to regulate TAMs polarization to inhibit the growth of non-small cell lung cancer (NSCLC). Firstly, systems pharmacology approach was used to reveal the active components of SR targeting macrophages in TME through compound target prediction and target-microenvironment phenotypic association analysis. Secondly, in vitro experiment verified that WBB (wogonin, baicalein and baicalin), major active ingredients of SR are significantly related to macrophages and survival, initiated macrophages programming to M1-like macrophages to promoted the apoptosis of tumor cells. Finally, we evidenced that WBB effectively inhibited tumor growth in LLC (Lewis lung carcinoma) tumor-bearing mice and increased the infiltration of M1-type macrophages in TME. Overall, the systems pharmacology strategy offers a paradigm to understand the mechanism of polypharmacology of natural products targeting TME.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunidade Inata/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Farmacologia em Rede , Macrófagos Associados a Tumor/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Bases de Dados Genéticas , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Células RAW 264.7 , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor. Compared with previous treatment modalities, such as amputation, more recent comprehensive treatment modalities based on neoadjuvant chemotherapy combined with limb salvage surgery have improved the survival rates of patients. Osteosarcoma treatment has, however, not further improved in recent years. Therefore, attention has shifted to the tumor microenvironment (TME) in which osteosarcoma cells are embedded. Therapeutic targets in the TME may be key to improving osteosarcoma treatment. Tumor-associated macrophages (TAMs) are the most common immune cells within the TME. TAMs in osteosarcoma may account for over 50% of the immune cells, and may play important roles in tumorigenesis, angiogenesis, immunosuppression, drug resistance and metastasis. Knowledge on the role of TAMs in the development, progression and treatment of osteosarcoma is gradually improving, although different or even opposing opinions still remain. CONCLUSIONS: TAMs may participate in the malignant progression of osteosarcoma through self-polarization, the promotion of blood vessel and lymphatic vessel formation, immunosuppression, and drug resistance. Besides, various immune checkpoint proteins expressed on the surface of TAMs, such as PD-1 and CD47, provide the possibility of the application of immune checkpoint inhibitors. Several clinical trials have been carried out and/or are in progress. Mifamotide and the immune checkpoint inhibitor Camrelizumab were both found to be effective in prolonging progression-free survival. Thus, TAMs may serve as attractive therapeutic targets. Targeting TAMs as a complementary therapy is expected to improve the prognosis of osteosarcoma. Further efforts may be made to identify potential beneficiaries of TAM-targeted therapies.
Assuntos
Neoplasias Ósseas/imunologia , Osteossarcoma/imunologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Neoplasias Ósseas/patologia , Progressão da Doença , Humanos , Osteossarcoma/patologia , Macrófagos Associados a Tumor/patologiaRESUMO
The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.
Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/toxicidade , Sinergismo Farmacológico , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ratos , Receptores CXCR4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cancer immunotherapy can boost the immune response of patients to eliminate tumor cells and suppress tumor metastasis and recurrence. However, immunotherapy resistance and the occurrence of severe immune-related adverse effects are clinical challenges that remain to be addressed. The tumor microenvironment plays a crucial role in the therapeutic efficacy of cancer immunotherapy. Injectable hydrogels have emerged as powerful drug delivery platforms offering good biocompatibility and biodegradability, minimal invasion, convenient synthesis, versatility, high drug-loading capacity, controlled drug release, and low toxicity. In this review, we summarize the application of injectable hydrogels as a unique platform for targeting the immunosuppressive tumor microenvironment.
Assuntos
Hidrogéis , Hospedeiro Imunocomprometido/efeitos dos fármacos , Terapia de Alvo Molecular , Neoplasias/imunologia , Neoplasias/terapia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais , Estudos Clínicos como Assunto , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/imunologia , Resultado do Tratamento , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
Background Anaplastic thyroid cancer (ATC) is aggressive with a poor prognosis, partly because of the immunosuppressive microenvironment created by tumor-associated macrophages (TAMs). Purpose To understand the relationship between TAM infiltration, tumor vascularization, and corresponding drug delivery by using ferumoxytol-enhanced MRI and macrin in an ATC mouse model. Materials and Methods ATC tumors were generated in 6-8-week-old female B6129SF1/J mice through intrathyroid injection to model orthotopic tumors, or intravenously to model hematogenous metastasis, and prospectively enrolled randomly into treatment cohorts (n = 94 total; August 1, 2018, to January 15, 2020). Mice were treated with vehicle or combined serine/threonine-protein kinase B-Raf (BRAF) kinase inhibitor (BRAFi) and anti-PDL1 antibody (aPDL1). A subset was cotreated with therapies, including an approximately 70-nm model drug delivery nanoparticle (DDNP) to target TAM, and an antibody-neutralizing colony stimulating factor 1 receptor (CSF1R). Imaging was performed at the macroscopic level with ferumoxytol-MRI and microscopically with macrin. Genetically engineered BrafV600E/WT p53-null allografts were used and complemented by a GFP-transgenic derivative and human xenografts. Tumor-bearing organs were processed by using tissue clearing and imaged with confocal microscopy and MRI. Two-tailed Wilcoxon tests were used for comparison (≥five per group). Results TAM levels were higher in orthotopic thyroid tumors compared with pulmonary metastatic lesions by 79% ± 23 (standard deviation; P < .001). These findings were concordant with ferumoxytol MRI, which showed 136% ± 88 higher uptake in thyroid lesions (P = .02) compared with lung lesions. BRAFi and aPDL1 combination therapy resulted in higher tumor DDNP delivery by 39% ± 14 in pulmonary lesions (P = .004). Compared with the untreated group, tumors following BRAFi, aPDL1, and CSF1R-blocking antibody combination therapy did not show greater levels of TAM or DDNP (P = .82). Conclusion In a mouse model of anaplastic thyroid cancer, ferumoxytol MRI showed 136% ± 88 greater uptake in orthotopic thyroid tumors compared with pulmonary lesions, which reflected high vascularization and greater tumor-associated macrophage (TAM) levels. Serine/threonine-protein kinase B-Raf inhibitor and anti-programmed death ligand 1 antibody elicited higher local TAM levels and 43% ± 20 greater therapeutic nanoparticle delivery but not higher vascularization in pulmonary tumors. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Luker in this issue.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Carcinoma Anaplásico da Tireoide/diagnóstico por imagem , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados/imunologia , Antineoplásicos/imunologia , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Óxido Ferroso-Férrico , Imunidade/imunologia , Camundongos , Nanopartículas , Proteínas Proto-Oncogênicas B-raf/imunologia , Carcinoma Anaplásico da Tireoide/imunologia , Macrófagos Associados a Tumor/imunologiaRESUMO
Regular exercise reduces the risk of cancer. One potential mechanism for this efficacy is improved antitumor immunity. This is an important issue because evading immune destruction is a hallmark of cancer and immunotherapy is reshaping cancer treatment. Here we review recent developments reported by Wennerberg et al., Garritson et al., Martín-Ruiz et al., and Rundqvist et al. on the effects of exercise on anticancer immune cell effectors.
Assuntos
Terapia por Exercício/métodos , Inibidores de Checkpoint Imunológico/farmacologia , Vigilância Imunológica/genética , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Terapia Combinada/métodos , Exercício Físico/fisiologia , Regulação da Expressão Gênica/imunologia , Saúde Holística , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Vigilância Imunológica/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologiaRESUMO
In the current study, we developed a synergistic chemo-immunotherapy using doxorubicin (Dox) and a natural polysaccharide as immunomodulator. First, we isolated a polysaccharide (MPW) from the root of Lepidium meyenii Walp. (maca) and characterized its chemical properties. MPW contains â 4) -α-D-Glcp- (1 â glycosidic bonds, while the terminal α-D-Glcp- (1 â group is connected to the main chain through an O-6 bond. This polysaccharide was then modified by cationization (C-MPW) to enhance immunoregulatory activity. MPW and C-MPW were combined with Dox and their chemo-immunotherapy effects on 4T1 tumor-bearing mice were assessed. Results indicated that the combination of MPW/C-MPW exerted a stronger anti-tumor effect than Dox alone, while reducing systemic toxicity and inhibiting tumor metastasis. In addition, MPW and C-MPW exerted tumor immunotherapy effects through the NF-κB, STAT1, and STAT3 signaling pathways, redirecting TAMs to the M1 phenotype that facilitates immunological responses against tumors. As a result, the immunosuppressive tumor microenvironment was remodeled into an immune-activated state due to enhanced secretion of IL-12, TNF-α, and INF-γ. Moreover, C-MPW exerted a stronger immunomodulatory effect than MPW. In conclusion, MPW and its cationic derivative are promising tools for cancer immunotherapy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carboidratos da Dieta/farmacologia , Fatores Imunológicos , Lepidium/química , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Macrófagos Associados a Tumor/imunologia , Animais , Apoptose , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Citocinas/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Células Tumorais Cultivadas , Macrófagos Associados a Tumor/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Resveratrol (3,4',5 trihydroxystilbene) is a naturally occurring non-flavonoid polyphenol. It has various pharmacological effects including antioxidant, anti-diabetic, anti-inflammatory and anti-cancer. Many studies have given special attention to different aspects of resveratrol anti-cancer properties and proved its high efficiency in targeting multiple cancer hallmarks. Tumor microenvironment has a critical role in cancer development and progression. Tumor cells coordinate with a cast of normal cells to aid the malignant behavior of cancer. Many cancer supporting players were detected in tumor microenvironment. These players include blood and lymphatic vessels, infiltrating immune cells, stromal fibroblasts and the extracellular matrix. Targeting tumor microenvironment components is a promising strategy in cancer therapy. Resveratrol with its diverse biological activities has the capacity to target tumor microenvironment by manipulating the function of many components surrounding cancer cells. This review summarizes the targets of resveratrol in tumor microenvironment and the mechanisms involved in this targeting. Studies discussed in this review will participate in building a solid ground for researchers to have more insight into the mechanism of action of resveratrol in tumor microenvironment.
Assuntos
Neoplasias/tratamento farmacológico , Resveratrol/uso terapêutico , Microambiente Tumoral , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Citocinas/metabolismo , Humanos , Neoplasias/patologia , Neoplasias/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/química , Macrófagos Associados a Tumor/citologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Jian-pi-yang-zheng Decoction (JPYZ) is a traditional Chinese medicine that is used for the treatment of advanced gastric cancer, and it shows good efficacy in patients. A previous study indicated that JPYZ inhibited the progression of gastric cancer via the regulation of tumor-associated macrophages (TAMs), but the underlying molecular target of JPYZ regulation of TAMs has not been determined. The present study used modified-JPYZ (mJPYZ) to extend our investigation of gastric cancer. Our results showed that mJPYZ inhibited gastric cancer progression in vivo and in vitro. We found that mJPYZ decreased the activity of PI3-kinase γ (PI3Kγ) in TAMs, reduced the anti-inflammatory factor IL-10 and increased the expression of pro-inflammatory cytokines, such as TNF-α and IL-1ß, which ultimately promoted the conversion of TAMs from M2 to M1. Our findings also indicated that mJPYZ inhibited the growth and metastasis of gastric cancer by alleviating the unfavorable differentiation of TAMs via the PI3Kγ signaling cascades. In conclusion, the present findings indicated that mJPYZ inhibited gastric cancer cell EMT via PI3Kγ-dependent TAM reprogramming, which eventually suppressed gastric cancer growth and metastasis. Our study provides an underlying mechanism of a Chinese medicine in the treatment of gastric cancer via PI3Kγ in macrophages.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Macrófagos Associados a Tumor/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Técnicas de Cocultura , Citocinas/metabolismo , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Metástase Neoplásica , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Células THP-1 , Microambiente Tumoral , Macrófagos Associados a Tumor/enzimologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologiaRESUMO
Skin diseases bring great psychological and physical impacts on patients, however, a considerable number of skin diseases still lack effective treatments, such as psoriasis, systemic lupus erythematosus, melanoma and so on. Receptor-interacting serine threonine kinase 1 (RIPK1) plays an important role in cell death, especially necroptosis, associated with inflammation and tumor. As many molecules modulate the ubiquitination of RIPK1, disruption of this checkpoint can lead to skin diseases, which can be ameliorated by RIPK1 inhibitors. This review will focus on the molecular mechanism of RIPK1 activation in inflammation as well as the current knowledges on the contribution of RIPK1 in skin diseases.
Assuntos
Dermatite/imunologia , Necroptose/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Neoplasias Cutâneas/imunologia , Animais , Ensaios Clínicos Fase II como Assunto , Dermatite/tratamento farmacológico , Dermatite/genética , Dermatite/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Imidazóis/farmacologia , Indóis/farmacologia , Camundongos , Camundongos Knockout , Necroptose/efeitos dos fármacos , Necroptose/genética , Oxazepinas/farmacologia , Oxazepinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Ratos , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Triazóis/farmacologia , Triazóis/uso terapêutico , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Ubiquitinação/imunologiaRESUMO
Increasing evidence indicates that the inflammatory tumor microenvironment can lead to cancer cell metastasis. Shikonin, which is extracted from the Chinese herb Zicao (the dried root of Lithospermum erythrorhizon), possesses various pharmacological effects, but its effect on tumor metastasis in the inflammatory microenvironment remains unknown. In the present study, we aimed to investigate the potential effect of shikonin on tumor metastasis in an inflammatory microenvironment as well as the underlying molecular mechanisms. It was found that, in the inflammatory microenvironment simulated by THP1 cell conditioned medium (THP1CM) in vitro, shikonin significantly inhibited the epithelialmesenchymal transition (EMT), migration and invasion of human lung adenocarcinoma cell lines A549 and H1299. In addition, we found that interleukin6 (IL6), which is expressed in THP1CM, promoted the EMT of lung adenocarcinoma cells, and shikonin markedly inhibited IL6induced EMT and cell motility. Moreover, shikonin inhibited IL6induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), prevented phosphorylated STAT3 (pSTAT3) translocation into the nucleus, and suppressed pSTAT3 transactivation activity. Additionally, it was found that shikonin inhibited lung metastasis, EMT and expression of pSTAT3 of A549 cells in vivo. Furthermore, IL6 levels in human lung adenocarcinoma tissues were significantly associated with tumornodemetastasis stage and lymph node metastasis, and its expression was correlated with tumorassociated macrophage (TAM) infiltration. Together, these results suggest that shikonin suppresses the migration and invasion of human lung adenocarcinoma cells in an inflammatory microenvironment involving the IL6/STAT3 signaling pathway.
Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Metástase Linfática/tratamento farmacológico , Naftoquinonas/farmacologia , Células A549 , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/secundário , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/imunologia , Feminino , Humanos , Interleucina-6/análise , Interleucina-6/metabolismo , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Metástase Linfática/imunologia , Masculino , Pessoa de Meia-Idade , Naftoquinonas/uso terapêutico , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: There is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Immunotherapy is promising especially when combined with traditional therapies. This study aimed to investigate the immunomodulatory function of an approved Chinese medicine formula, compound kushen injection (CKI), and its anti-HCC efficiency in combination with low-dose sorafenib. METHODS: Growth of two murine HCC cells was evaluated in an orthotopic model, a subcutaneous model, two postsurgical recurrence model, and a tumor rechallenge model with CKI and low-dose sorafenib combination treatment. In vivo macrophage or CD8+ T cell depletion and in vitro primary cell coculture models were used to determine the regulation of CKI on macrophages and CD8+ T cells. RESULTS: CKI significantly enhanced the anticancer activity of sorafenib at a subclinical dose with no obvious side effects. CKI and sorafenib combination treatment prevented the postsurgical recurrence and rechallenged tumor growth. Further, we showed that CKI activated proinflammatory responses and relieved immunosuppression of tumor-associated macrophages in the HCC microenvironment by triggering tumor necrosis factor receptor superfamily member 1 (TNFR1)-mediated NF-κB and p38 MAPK signaling cascades. CKI-primed macrophages significantly promoted the proliferation and the cytotoxic ability of CD8+ T cells and decreased the exhaustion, which subsequently resulted in apoptosis of HCC cells. CONCLUSIONS: CKI acts on macrophages and CD8+ T cells to reshape the immune microenvironment of HCC, which improves the therapeutic outcomes of low-dose sorafenib and avoids adverse chemotherapy effects. Our study shows that traditional Chinese medicines with immunomodulatory properties can potentiate chemotherapeutic drugs and provide a promising approach for HCC treatment.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Terapia de Imunossupressão , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Sorafenibe/farmacologia , Macrófagos Associados a Tumor/imunologia , Animais , Antineoplásicos/farmacologia , Apoptose , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Células Tumorais Cultivadas , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Diffuse large cell B cell lymphoma (DLBCL) accounts for approximately 30%-40% of all non-Hodgkin lymphoma (NHL) cases. Current first line DLBCL treatment results in long-term remission in more than 60% of cases. However, those patients with primary refractory disease or early relapse exhibit poor prognosis, highlighting a requirement for alternative therapies. Our aim was to develop a novel model of DLBCL that facilitates in vitro testing of current and novel therapies by replicating key components of the tumor microenvironment (TME) in a three-dimensional (3D) culture system that would enable primary DLBCL cell survival and study ex vivo. The TME is a complex ecosystem, comprising malignant and non-malignant cells, including cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) whose reciprocal crosstalk drives tumor initiation and growth while fostering an immunosuppressive milieu enabling its persistence. The requirement to recapitulate, at least to some degree, this complex, interactive network is exemplified by the rapid cell death of primary DLBCL cells removed from their TME and cultured alone in vitro. Building on previously described methodologies to generate lymphoid-like fibroblasts from adipocyte derived stem cells (ADSC), we confirmed lymphocytes, specifically B cells, interacted with this ADSC-derived stroma, in the presence or absence of monocyte-derived macrophages (MDM), in both two-dimensional (2D) cultures and a 3D collagen-based spheroid system. Furthermore, we demonstrated that DLBCL cells cultured in this system interact with its constituent components, resulting in their improved viability as compared to ex-vivo 2D monocultures. We then assessed the utility of this system as a platform to study therapeutics in the context of antibody-directed phagocytosis, using rituximab as a model immunotherapeutic antibody. Overall, we describe a novel 3D spheroid co-culture system comprising key components of the DLBCL TME with the potential to serve as a testbed for novel therapeutics, targeting key cellular constituents of the TME, such as CAF and/or TAM.