RESUMO
AIM OF THE STUDY: To evaluate the in vitro and in vivo anti-metastasis efficacy of Jianpi Yangzheng (JPYZ) decoction against gastric cancer (GC) and its potential mechanisms. MATERIALS AND METHODS: The distant metastasis of GC cells administered via tail vein injection was assessed using the pre-metastatic niche (PMN) model. 16S rRNA sequencing and GC-MS/MS were applied to determine the component of the gut microbiota and content of short-chain fatty acids (SCFAs) in feces of mice, respectively. The proportion of myeloid-derived suppressor cells (MDSCs) in the lung was evaluated by flow cytometry and immunofluorescence. Serum or tissue levels of inflammation factors including IL-6, IL-10 and TGF-ß were determined by ELISA or Western blot respectively. RESULTS: Injecting GC cells into the tail vein of mice led to the development of lung metastases and also resulted in alterations in the composition of gut microbiota and the levels of SCFAs produced. Nevertheless, JPYZ treatment robustly impeded the effect of GC cells administration. Mechanically, JPYZ treatment not only prevented the alteration in gut microbiota structure, but also restored the SCFAs content induced by GC cells administration. Specifically, JPYZ treatment recovered the relative abundance of genera Moryella, Helicobacter, Lachnoclostridium, Streptococcus, Tuzzerella, GCA-900066575, uncultured_Lachnospiraceae, Rikenellaceae_RC9_gut_group and uncultured_bacterium_Muribaculaceae to near the normal control levels. In addition, JPYZ abrogated MDSCs accumulation in the lung tissue and blocked inflammation factors overproduction in the serum and lung tissues, which subsequently impede the formation of the immunosuppressive microenvironment. Correlation analysis revealed that the prevalence of Rikenellaceae in the model group exhibited a positive correlation with MDSCs proportion and inflammation factor levels. Conversely, the scarcity of Muribaculaceae in the model group showed a negative correlation with these parameters. This suggests that JPYZ might exert an influence on the gut microbiota and their metabolites, such as SCFAs, potentially regulating the formation of the PMN and consequently impacting the outcome of GC metastasis. CONCLUSION: These findings suggest that GC cells facilitate metastasis by altering the gut microbiota composition, affecting the production of SCFAs, and recruiting MDSCs to create a pro-inflammatory pre-metastatic niche. JPYZ decoction counteracts this process by reshaping the gut microbiota structure, enhancing SCFA production, and inhibiting the formation of the pre-metastatic microenvironment, thereby exerting an anti-metastatic effect.
Assuntos
Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Neoplasias Pulmonares , Células Supressoras Mieloides , Neoplasias Gástricas , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Células Supressoras Mieloides/efeitos dos fármacos , Linhagem Celular Tumoral , Ácidos Graxos Voláteis/metabolismo , Camundongos Endogâmicos BALB C , Humanos , RNA Ribossômico 16S , Masculino , Fezes/microbiologia , FemininoRESUMO
OBJECTIVES: To investigate the mechanism of Xuanhusuo powder (XHSP) inhibiting the differentiation of spleen myeloid-derived suppressor cells (MDSCs) in breast cancer mice. METHODS: Forty-eight BALB/c female mice aged 4-5 weeks were selected, 6 of them were in normal control group, while others were in tumor-bearing models established by orthotopic injection of 4T1 cells into the subcutaneous fat pad of the second pair of left mammary glands. The tumor-bearing mice were divided into granulocyte colony stimulating factor (G-CSF) control group, G-CSF knock-down group, model control group, XHSP small dose group, XHSP medium dose group, XHSP high dose group, and cyclophosphamide (CTX) group, with 6 mice in each group. G-CSF control group and G-CSF knock-down group were constructed by stably transfecting 4T1 cells established by shRNA lentivirus combined with puromycin selection. 48 h after the model was established, XHSP small, medium, high dose group were given 2, 4, 8 g·kgï¼1·dï¼1 intragastric administration once a day, respectively. CTX was given 30 mg/kg by intraperitoneal injection, once every other day. The other groups were given an equal volume of 0.5% hydroxymethylcellulose sodium. The drugs in each group were continuously administered for 25 d. Histological changes in spleen were observed by HE staining, the proportion of MDSCs subsets in the spleen were detected by flow cytometry, the co-expression of CD11b and Ly6G in the spleen was detected by immunofluorescence, and the concentration of G-CSF in peripheral blood was detected by ELISA. The spleen of tumor-bearing mice was co-cultured with 4T1 stably transfected cell lines in vitro, treated with XHSP (30 µg/mL) for 24 h, and the co-expression of CD11b and Ly6G in the spleen was detected by immunofluorescence. 4T1 cells were treated by XHSP (10, 30, 100 µg/mL) for 12 h. The mRNA level of G-CSF was detected by realtime RT-PCR. RESULTS: Compared with normal mice, the red pulp of the spleen in tumor-bearing mice was widened with megakaryocyte infiltration. The proportion of spleen polymorphonucleocyte-like MDSCs (PMN-MDSCs) was significantly increased (P<0.01) and the co-expression of CD11b and Ly6G was increased, and the concentration of G-CSF in peripheral blood was significantly increased (P<0.01). However, XHSP could significantly reduce the proportion of PMN-MDSCs (P<0.05) and the co-expression of CD11b and Ly6G in the spleen, down-regulate the mRNA level of G-CSF in 4T1 cells (P<0.01). The concentration of G-CSF in peripheral blood of tumor-bearing mice also decreased (P<0.05) and tumor volume was reduced and splenomegaly was improved (all P<0.05). CONCLUSIONS: XHSP may play an anti-breast cancer role by down-regulating G-CSF, negatively regulating the differentiation of MDSCs, and reconstruct the spleen myeloid microenvironment.
Assuntos
Antineoplásicos , Neoplasias da Mama , Medicamentos de Ervas Chinesas , Animais , Camundongos , Medicamentos de Ervas Chinesas/administração & dosagem , Baço/citologia , Baço/efeitos dos fármacos , Células Supressoras Mieloides/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Feminino , Neoplasias da Mama/tratamento farmacológico , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Antineoplásicos/administração & dosagemRESUMO
5-Fluorouracil (5-FU)-based chemotherapy is the first-line recommended regimen in colorectal cancer (CRC), but resistance limits its clinical application. Andrographolide sulfonate, a traditional Chinese medicine, is mainly used to treat infectious diseases. In the present study, we reported that andrographolide sulfonate could significantly inhibit the growth of transplanted CT26 colon cancer in mice and improve survival when combined with 5-FU. Furthermore, TUNEL assay and immunohistochemistry analysis of proliferating cell nuclear antigen, Ki-67 and p-STAT3 confirmed that co-treatment could inhibit tumor proliferation and promote apoptosis. In tumor tissues of groups that received 5-FU and andrographolide sulfonate, CD4+ and CD8+ T cell infiltration was increased, and the expression of IFN-γ and Granzyme B detected by immunohistochemistry and qPCR was upregulated, reflecting improved antitumor immunity. Finally, we verified that 5-FU significantly activated the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in myeloid-derived suppressor cells (MDSCs) and that andrographolide sulfonate reversed this process to sensitize cells to 5-FU. In summary, andrographolide sulfonate synergistically enhanced antitumor effects and improved antitumor immunity by inhibiting 5-FU-induced NLRP3 activation in MDSCs. These findings provide a novel strategy to address 5-FU resistance in the treatment of CRC.
Assuntos
Anti-Inflamatórios/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Diterpenos/administração & dosagem , Fluoruracila/administração & dosagem , Células Supressoras Mieloides/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Sinergismo Farmacológico , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases.
Assuntos
Acetilcisteína/farmacologia , Adjuvantes Imunológicos/farmacologia , Eflornitina/farmacologia , Hepatite C/imunologia , Imunidade Ativa/efeitos dos fármacos , Proteínas não Estruturais Virais/imunologia , Animais , Proliferação de Células , Células Cultivadas , Feminino , Imunogenicidade da Vacina/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Óxido Nítrico/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Vacinas contra Hepatite Viral/imunologiaRESUMO
The application of traditional chemotherapy drugs for lung cancer has obvious limitations, such as toxic side effects, uncontrolled drug-release, poor bioavailability, and drug-resistance. Thus, to address the limitations of free drugs and improve treatment effects, we developed novel T7 peptide-modified nanoparticles (T7-CMCS-BAPE, CBT) based on carboxymethyl chitosan (CMCS), which is capable of targeted binding to the transferrin receptor (TfR) expressed on lung cancer cells and precisely regulating drug-release according to the pH value and reactive oxygen species (ROS) level. The results showed that the drug-loading content of docetaxel (DTX) and curcumin (CUR) was approximately 7.82% and 6.48%, respectively. Good biosafety was obtained even when the concentration was as high as 500 µg/mL. More importantly, the T7-CMCS-BAPE-DTX/CUR (CBT-DC) complexes exhibited better in vitro and in vivo anti-tumor effects than DTX monotherapy and other nanocarriers loaded with DTX and CUR alone. Furthermore, we determined that CBT-DC can ameliorate the immunosuppressive micro-environment to promote the inhibition of tumor growth. Collectively, the current findings help lay the foundation for combinatorial lung cancer treatment.
Assuntos
Antineoplásicos/uso terapêutico , Curcumina/uso terapêutico , Docetaxel/uso terapêutico , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Quitosana/análogos & derivados , Quitosana/metabolismo , Quitosana/farmacocinética , Quitosana/toxicidade , Curcumina/química , Curcumina/farmacocinética , Docetaxel/química , Docetaxel/farmacocinética , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Pulmão/patologia , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Células Supressoras Mieloides/efeitos dos fármacos , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Non-small-cell lung cancer (NSCLC) remains the most common malignancy with the highest morbidity and mortality worldwide. In our previous study, we found that a classic traditional Chinese medicine (TCM) formula Ze-Qi-Tang (ZQT), which has been used in the treatment of respiratory diseases for thousands of years, could directly inhibit the growth of human NSCLC cells via the p53 signaling pathway. In this study, we explored the immunomodulatory functions of ZQT. We found that ZQT significantly prolonged the survival of orthotopic lung cancer model mice by modulating the tumor microenvironment (TME). ZQT remarkably reduced the number of MDSCs (especially G-MDSCs) and inhibited their immunosuppressive activity by inducing apoptosis in these cells via the STAT3/S100A9/Bcl-2/caspase-3 signaling pathway. When G-MDSCs were depleted, the survival promotion effect of ZQT and its inhibitory effect on lung luminescence signal disappeared in tumor-bearing mice. This is the first study to illustrate the immunomodulatory effect of ZQT in NSCLC and the underlying molecular mechanism.
Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Granulócitos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Medicina Tradicional Chinesa , Células Supressoras Mieloides/efeitos dos fármacos , Animais , Calgranulina B/fisiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Caspase 3/fisiologia , Linhagem Celular Tumoral , Medicamentos de Ervas Chinesas/uso terapêutico , Granulócitos/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/patologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/efeitos dos fármacos , Microambiente TumoralRESUMO
BACKGROUND: PD-1/PD-L1 engagement and overexpression of galectin-3 (Gal-3) are critical mechanisms of tumor-induced immune suppression that contribute to immunotherapy resistance. We hypothesized that Gal-3 blockade with belapectin (GR-MD-02) plus anti-PD-1 (pembrolizumab) would enhance tumor response in patients with metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC). METHODS: We performed a phase I dose escalation study of belapectin+pembrolizumab in patients with advanced MM or HNSCC (NCT02575404). Belapectin was administered at 2, 4, or 8 mg/kg IV 60 min before pembrolizumab (200 mg IV every 3 weeks for five cycles). Responding patients continued pembrolizumab monotherapy for up to 17 cycles. Main eligibility requirements were a functional Eastern Cooperative Oncology Group status of 0-2, measurable or assessable disease, and no active autoimmune disease. Prior T-cell checkpoint antibody therapy was permitted. RESULTS: Objective response was observed in 50% of MM (7/14) and and 33% of HNSCC (2/6) patients. Belapectin+pembrolizumab was associated with fewer immune-mediated adverse events than anticipated with pembrolizumab monotherapy. There were no dose-limiting toxicities for belapectin within the dose range investigated. Significantly increased effector memory T-cell activation and reduced monocytic myeloid-derived suppressor cells (M-MDSCs) were observed in responders compared with non-responders. Increased baseline expression of Gal-3+ tumor cells and PD-1+CD8+ T cells in the periphery correlated with response as did higher serum trough levels of pembrolizumab. CONCLUSIONS: Belapectin+pembrolizumab therapy has activity in MM and HNSCC. Increased Gal-3 expression, expansion of effector memory T cells, and decreased M-MDSCs correlated with clinical response. Further investigation is planned.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Sanguíneas/antagonistas & inibidores , Galectinas/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Pectinas/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas Sanguíneas/imunologia , Feminino , Galectinas/imunologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Células T de Memória/efeitos dos fármacos , Células T de Memória/imunologia , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/imunologia , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Pectinas/efeitos adversos , Receptor de Morte Celular Programada 1/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Fatores de Tempo , Resultado do TratamentoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Shuangshen granules (SSG) have been used to treat lung cancer patients with Qi deficiency and blood stasis for decades. According to clinical experience, SSG indeed improve the quality of life and prolong the survival time of patients with lung cancer after surgery. Each of the components herbs was proved to be effective in anti-cancer therapy. Both the American ginseng and notoginseng belong to genus Panax of the family Araliaceae. Preclinical and clinical studies demonstrated that ginsenosides of them have anti- or preventive activities to various tumors, including cancers of gastric, breast, liver, lung, ovarian, colon, melanoma and leukemia. PDS, such as ginsenoside Rb1, and PTS, such as ginsenoside Rg1 are the main anticancer compositions. Cordyceps sinensis had also been found effective in inhibiting tumour growth and metastasis, especially on tumour associated immune cells, such as macrophages. However, limited information is available regarding potential mechanisms of SSG. Myeloid-derived suppressor cell (MDSC)-mediated immunosuppression, which is closely associated with poor clinical outcomes in cancer patients, may be the target of SSG, which regulate immune function. AIM OF THE STUDY: The present study aimed to explore whether SSG attenuate the differentiation of bone marrow cells (BMCs) into MDSCs by blocking the mTOR signalling, leading to the suppression of lung metastasis. MATERIALS AND METHODS: First, we observed the differentiation of BMCs into MDSCs in vitro and in vivo. BMCs were cultured alone or co-cultured with Lewis lung carcinoma (LLC) cell supernatant in vitro. The effects of different concentrations of SSG, or LLC cell supernatant as a control, on BMC differentiation were detected by flow cytometry and western blotting. Male C57BL/6J mice were subcutaneously implanted with LLC cells, and SSG were administered by gavage twice daily before and after implantation for 7 or 14 days, respectively. The tumour weight, proportion of MDSCs, presence of CD11b+Ly6C+Ly6G- and CD11b+Ly6C+Ly6G+ cells in the bone marrow, blood, and lungs, as well as the expression levels of differentiation-related proteins in the bone marrow and lungs were evaluated. RESULTS: SSG attenuated the differentiation of BMCs into MDSCs, and reduced the fraction of CD11b+Ly6C+Ly6G+ cells by inhibiting the mTOR/S6K1/Myc signalling pathway. In vivo, SSG attenuated differentiation-associated protein markers and reduced the fractions of MDSCs and CD11b+Ly6C+Ly6G+ cells in the bone marrow, blood, and lungs. In addition, SSG administration reduced the tumour weight and inhibited lung metastasis. CONCLUSIONS: SSG may reduce lung metastasis by attenuating BMC differentiation into CD11b+Ly6C+Ly6G+ cells by inhibiting mTOR signalling in vitro and in vivo.
Assuntos
Células da Medula Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/fisiologia , Neoplasias Experimentais , Fitoterapia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genéticaRESUMO
Melanoma is one of the most aggressive malignancies and its treatment remains challenging due to its highly metastatic property and availability of limited effective drugs. In addition, immunosuppresive tumor microenvironment (TME) has been identified as major barrier to evoke anti-tumor response in melanoma. Recent studies revealed that immunosuppressive TME is directly correlated with heightened activations of T regulatory cells (Tregs) and Myeloid derived suppressor cells (MDSCs) functions. In this study, we investigated the anti-cancer effect of a triterpenoid, glycyrrhizic acid (GA) on melanoma. Our study revealed that GA not only exhibited anti-proliferative effects on melanoma cells it significantly restricted progression of melanoma tumor. However, the therapeutic efficacy of GA in impressive regression of tumor was found to be directly correlated with induction of apoptosis and modulation of cytokines from Th2 to Th1 type. To unravel the mechanism of anti-melanoma effect of GA, it has been delineated that GA inhibits pSTAT3 to evade anti-tumor suppressive function of Tregs and MDSCs. Downregulation of FOXP3, GITR and CTLA4 in tumor-infiltrating Tregs and inhibition of Cox2, PGE2 and Arginase 1 in intra-tumoral MDSC were evidenced as some of the key events during therapeutic intervention of GA in melanoma management. Moreover, GA effectively restricted advanced stage solid tumor while used in combination with Mycobacterium indicus pranii, a known immunomodulator, which alone is reported to be ineffective to restrict advanced stage solid tumor. Thus, our findings may open up a novel insight of GA as a promising agent in cancer immunotherapy or adjuvant therapy in future.
Assuntos
Antineoplásicos/farmacologia , Ácido Glicirrízico/farmacologia , Melanoma/imunologia , Mycobacterium , Células Supressoras Mieloides/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/imunologia , Feminino , Ácido Glicirrízico/uso terapêutico , Humanos , Imunoterapia , Melanoma/tratamento farmacológico , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Fator de Transcrição STAT3/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
Immune checkpoint inhibitors are becoming standard treatments in several cancer types, profoundly changing the prognosis of a fraction of patients. Currently, many efforts are being made to predict responders and to understand how to overcome resistance in non-responders. Given the crucial role of myeloid cells as modulators of T effector cell function in tumors, it is essential to understand their impact on the clinical outcome of immune checkpoint blockade and on the mechanisms of immune evasion. In this review we focus on the existing clinical evidence of the relation between the presence of myeloid cell subsets and the response to anti-PD(L)1 and anti-CTLA-4 treatment. We highlight how circulating and tumor-infiltrating myeloid populations can be used as predictive biomarkers for immune checkpoint inhibitors in different human cancers, both at baseline and on treatment. Moreover, we propose to follow the dynamics of myeloid cells during immunotherapy as pharmacodynamic biomarkers. Finally, we provide an overview of the current strategies tested in the clinic that use myeloid cell targeting together with immune checkpoint blockade with the aim of uncovering the most promising approaches for effective combinations.
Assuntos
Biomarcadores , Inibidores de Checkpoint Imunológico/farmacologia , Proteínas de Checkpoint Imunológico/metabolismo , Células Mieloides/metabolismo , Animais , Estudos Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Terapia de Alvo Molecular , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Resultado do TratamentoRESUMO
Baoyuan Jiedu (BYJD for short) decoction, a traditional Chinese medicine formula, is composed of Astragalus, Ginseng, Aconite root, Honeysuckle, Angelica, Licorice, which has the functions of nourishing qi and blood, enhancing immune function, improving quality of life and prolonging survival time of tumor patients. The present study aimed to investigate the effect and mechanism of BYJD decoction on reversing the pre-metastatic niche. We showed that BYJD decoction could prolong the survival time of 4T1 tumor-bearing mice. Moreover, we found that the BYJD decoction inhibited the formation of lung pre-metastatic niche and inhibited recruitment of myeloid derived suppressor cells (MDSCs) in the lung. Mechanistically, we showed that the proteins and genes expression of TGF-ß, Smad2, Smad3, p-Smad2/3, Smad4, CCL9 in the TGF-ß/CCL9 signaling pathway were suppressed by BYJD decoction. In line with the above findings, our results confirm that BYJD decoction inhibits the accumulation of MDSC in pre-metastatic niche of lung via TGF-ß/CCL9 pathway.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Quimiocinas CC/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Pulmonares/prevenção & controle , Pulmão/efeitos dos fármacos , Proteínas Inflamatórias de Macrófagos/metabolismo , Células Supressoras Mieloides/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Quimiocinas CC/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Proteínas Inflamatórias de Macrófagos/genética , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Carga Tumoral/efeitos dos fármacosRESUMO
Myeloid-derived suppressor cells (MDSCs) play a crucial role in immunosuppression in tumor-bearing hosts. MDSCs express arginase-I and indoleamine 2,3-dioxygenase; they suppress T-cell function by reducing the levels of l-arginine and l-tryptophan, respectively. We examined the anticancer effects of supplementation of these amino acids in CT26 colon carcinoma-bearing mice. Oral supplementation of l-arginine or l-tryptophan (30 mg/mouse) did not affect tumor growth, whereas oral supplementation of d-arginine was lethal. Supplementation of l-arginine showed a tendency to augment the efficacy of cyclophosphamide (CP). CP reduced the proportions of granulocytic MDSCs and increased the proportions of monocytic MDSCs in the spleen and tumor tissues of CT26-bearing mice. l-Arginine supplementation alone did not affect the MDSC subsets. CP treatment tended to reduce the plasma levels of l-arginine in CT26-bearing mice and significantly increased the number of tumor-infiltrating CD8+ T cells. In addition, l-arginine supplementation significantly increased the proportions of tumor peptide-specific CD8+ T cells in draining lymph nodes. Importantly, additional supplementation of l-arginine significantly increased the number of cured mice that were treated with CP and anti-PD-1 antibody. Totally, l-arginine supplementation shows promise for boosting the therapeutic efficacy of chemoimmunotherapy.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Antineoplásicos/farmacologia , Arginina/administração & dosagem , Suplementos Nutricionais , Aminoácidos/sangue , Animais , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Camundongos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Cancer immunotherapy is an emerging treatment strategy that modulates the immune system to fight against cancer. Although several immunotherapeutic agents have been utilized in the clinic for cancer treatment, low patient response rates and potential immune-related adverse events remain two major challenges. With the merits of delivery controllability and modular flexibility, nanomedicines provide opportunities to facilitate immunotherapies for clinical translation in a safe and effective manner. In this review, we discuss the convergence of nanomedicine with immunotherapy with a focus on molecular and nanoengineering approaches towards activatable cancer immunotherapy. These activatable nanoagents exert immunotherapeutic action only in response to internal or external stimuli. This allows them to locally reprogram the tumor microenvironment and activate antitumor immunity while reducing the incidence of immune-related adverse events. The category of activatable immunotherapeutic nanoagents are discussed along with an overview of their clinical translation prospects and challenges.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/terapia , Antineoplásicos Imunológicos , Terapia Combinada/métodos , Portadores de Fármacos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Imunoterapia , Linfócitos/efeitos dos fármacos , Magnetoterapia , Células Supressoras Mieloides/efeitos dos fármacos , Nanomedicina , Oxirredução , Fotoquimioterapia , Poliésteres/química , Polietilenoglicóis/química , Propriedades de Superfície , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/efeitos dos fármacos , Ondas UltrassônicasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Propolis is a natural product produced by honeybees used as a medicine at least to 300 BC. In the last decades, several studies showed biological and pharmacological properties of propolis, witch scientifically explains the empirical use for centuries. The anti-inflammatory activity of propolis with the purpose to reduce Th2 inflammation has been evaluated in allergic asthma. However, it remains to be determined how propolis negatively regulates the immune response after allergen re-exposure. AIM OF THE STUDY: We hypothesized that the anti-inflammatory activity of propolis is dependent on the induction of myeloid derived suppressor cells (MDSC) and regulatory T cells. MATERIALS AND METHODS: To assess this hypothesis, we used an ovalbumin-induced asthma model to evaluate the effect of EPP-AF® dry extract from Brazilian green propolis. RESULTS: Propolis treatment decreased pulmonary inflammation and mucus production as well as eosinophils and IL-5 in the broncoalveolar lavage. Propolis enhanced also in vitro differentiation and in vivo frequency of lung MDSC and CD4+Foxp3+ regulatory T cells. CONCLUSIONS: Together these results confirm the immunomodulatory potential of propolis during sensitization and challenge with allergen. In addition, the collecting findings show, for the first time, that propolis increases the frequency of MDSC and CD4+Foxp3+ regulatory T cells in the lungs, and suggest that it could be use as target for development of new immunotherapy or adjuvant immunotherapy for asthma.
Assuntos
Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Células Supressoras Mieloides/efeitos dos fármacos , Própole/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Alérgenos , Animais , Anti-Inflamatórios/farmacologia , Asma/induzido quimicamente , Asma/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Diferenciação Celular/efeitos dos fármacos , Feminino , Fatores Imunológicos/farmacologia , Imunoterapia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-5/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Ovalbumina , Própole/farmacologia , Linfócitos T Reguladores/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologiaRESUMO
Ginsenosides, the key components isolated from ginseng, have been extensively studied in antitumor treatment. Numerous studies have shown that ginsenosides have direct function in tumor cells through the induction of cancer cell apoptosis and the inhibition of cancer cell growth and enhance the antitumor immunity through the activation of cytotoxic T lymphocytes and natural killer cells. However, little is known about the function of ginsenosides on myeloid immunosuppressive cells including dendritic cells in tumor, tumor-associated macrophages, and myeloid-derived suppressor cells in the tumor microenvironments. Those myeloid immunosuppressive cells play important roles in promoting tumor angiogenesis, invasion, and metastasis. In the review, we summarize the regulatory functions of ginsenosides on myeloid immunosuppressive cells in tumor microenvironment, providing the novel therapeutic methods for clinical cancer treatment.
Assuntos
Ginsenosídeos/farmacologia , Imunossupressores/farmacologia , Células Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Linfócitos T Citotóxicos/efeitos dos fármacosRESUMO
BACKGROUNDMyeloid-derived suppressor cells (MDSCs) are elevated in the circulation of patients with glioblastoma (GBM), present in tumor tissue, and associated with poor prognosis. While low-dose chemotherapy reduces MDSCs in preclinical models, the use of this strategy to reduce MDSCs in GBM patients has yet to be evaluated.METHODSA phase 0/I dose-escalation clinical trial was conducted in patients with recurrent GBM treated 5-7 days before surgery with low-dose chemotherapy via capecitabine, followed by concomitant low-dose capecitabine and bevacizumab. Clinical outcomes, including progression-free and overall survival, were measured, along with safety and toxicity profiles. Over the treatment time course, circulating MDSC levels were measured by multiparameter flow cytometry, and tumor tissue immune profiles were assessed via time-of-flight mass cytometry.RESULTSEleven patients total were enrolled across escalating dose cohorts of 150, 300, and 450 mg bid. No serious adverse events related to the drug combination were observed. Compared with pretreatment baseline, circulating MDSCs were found to be higher after surgery in the 150-mg treatment arm and lower in the 300-mg and 450-mg treatment arms. Increased cytotoxic immune infiltration was observed after low-dose capecitabine compared with untreated GBM patients in the 300-mg and 450-mg treatment arms.CONCLUSIONSLow-dose, metronomic capecitabine in combination with bevacizumab was well tolerated in GBM patients and was associated with a reduction in circulating MDSC levels and an increase in cytotoxic immune infiltration into the tumor microenvironment.TRIAL REGISTRATIONClinicalTrials.gov NCT02669173.FUNDINGThis research was funded by the Cleveland Clinic, Case Comprehensive Cancer Center, the Musella Foundation, B*CURED, the NIH, the National Cancer Institute, the Sontag Foundation, Blast GBM, the James B. Pendleton Charitable Trust, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Capecitabine was provided in kind by Mylan Pharmaceuticals.
Assuntos
Antineoplásicos Imunológicos , Capecitabina , Glioblastoma/tratamento farmacológico , Células Supressoras Mieloides/efeitos dos fármacos , Adulto , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/administração & dosagem , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Capecitabina/administração & dosagem , Capecitabina/farmacologia , Capecitabina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that play an important role in immune evasion, PD-1/PD-L1 inhibitor tolerance and tumour progression. Therefore, MDSCs are potential targets for cancer immunotherapy. In this study, we screened an effective polymorphonuclear MDSC (PMN-MDSC) inhibitor from the Traditional Chinese Medicine Library and evaluated its synergistic antitumour effects with PD-1 inhibitor. METHODS: In the present study, we found that PMN-MDSCs accumulate heavily in the spleen and bone marrow of melanoma (B16-F10) tumour-bearing mice. Then, we determined the top 10 key proteins in the upregulated KEGG pathways of PMN-MDSCs in tumour-bearing mice through proteomics and Cytoscape analysis. The key proteins were then used as targets for the screening of PMN-MDSC inhibitors from the traditional Chinese Medicine Library (20000 compounds) through molecular docking and weight calculation of the docking score. Finally, the inhibitory effect of the inhibitor was verified through proteomics and metabolomics analysis in vitro and melanoma (B16-F10) and triple-negative breast cancer (4 T1) mouse tumour models in vivo. RESULTS: Traditional Chinese medicine saposhnikovia root extract Prim-O-glucosylcimifugin (POG) could bind well to the target proteins and inhibit the proliferation, metabolism and immunosuppressive ability of PMN-MDSCs by inhibiting arginine metabolism and the tricarboxylic acid cycle (TCA cycle). POG could also increase CD8 T-lymphocyte infiltration in the tumours and enhance the antitumour effect of PD-1 inhibitor in B16-F10 and 4 T1 mouse tumour models. CONCLUSIONS: POG was successfully screened from the traditional Chinese Medicine library as a PMN-MDSC inhibitor. POG exhibited a good synergistic antitumour effect with PD-1 inhibitor. This study provided a potential option for enhancing the efficacy of PD-1 inhibitors in clinical applications.
Assuntos
Anticorpos Monoclonais/farmacologia , Sinergismo Farmacológico , Melanoma Experimental/tratamento farmacológico , Monossacarídeos/farmacologia , Células Supressoras Mieloides/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Xantenos/farmacologia , Animais , Apoptose , Proliferação de Células , Feminino , Imunoterapia , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Receptor de Morte Celular Programada 1/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
INTRODUCTION: Lupus nephritis (LN) is a representative manifestation in systemic lupus erythematosus (SLE). Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of the SLE process. MDSC infiltration in the kidney as well as inflammation and oxidative stress provokes the acceleration and deterioration of LN. Nuclear factor E2-related factor 2 (Nrf2) is thought to be a major regulator of the antioxidant response. Baicalein is a flavonoid with known anti-inflammatory effects and antioxidant response. However, the effects of baicalein on MDSCs, inflammation, and oxidative stress are not evaluated in the development of pristane-induced LN in mice. METHODS: The renoprotective effect of baicalein was detected in a pristane-induced lupus mice model. NLRP3 inflammasome activation and NF-κB phosphorylation as well as reactive oxygen species (ROS) production and Nrf2 activation were examined. The percentages and function changes of MDSCs were measured. The possible mechanisms of the underlying effects of baicalein on ROS production and signaling pathways of Nrf2/heme-oxygenase (HO)-1, NLRP3 inflammasome, and NF-κB phosphorylation in lipopolysaccharide (LPS)-primed MDSCs were analyzed. RESULTS: Baicalein reduced proteinuria and attenuated renal function impairment and renal histopathology including intrinsic cell proliferation, cellular crescents, and podocyte injury as well as glomerulonephritis activity in lupus mice. Moreover, baicalein downregulated the activation of NLRP3 inflammasome and levels of ROS or NF-κB phosphorylation, and it enhanced Nrf2 activation. Of note, baicalein inhibited the expansion of MDSCs and improved the function of MDSCs in lupus mice. Through analyzing LPS-primed MDSCs in vitro, baicalein was found to exhibit cytoprotective effects coincident with the induction of Nrf2/HO-1 signaling and the suppression of the NLRP3 inflammasome. CONCLUSION: The data show that baicalein alleviates the symptoms of pristane-induced LN and suggest that the alleviation may be attributed to inhibition of MDSC expansion and regulation of the balance of the Nrf2/HO-1 signal and NLRP3 expression in MDSCs.
Assuntos
Flavanonas/uso terapêutico , Heme Oxigenase-1/metabolismo , Nefrite Lúpica/metabolismo , Proteínas de Membrana/metabolismo , Células Supressoras Mieloides/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Terpenos/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Imunossupressores/toxicidade , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/efeitos dos fármacos , Antagonistas de Prostaglandina/farmacologia , Antagonistas de Prostaglandina/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismoRESUMO
Glutamine metabolism and the mechanistic target of rapamycin (mTOR) pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. But the combined inhibition of both pathways was rarely investigated. This study investigated how inhibiting both glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) and mTOR with rapamycin affects immune cells and the arthritis in a mouse model. We revealed that rapamycin and DON additively suppressed CD4+ T cell proliferation, and both of them inhibited Th17 cell differentiation. While DON inhibited the differentiation of dendritic cells and macrophages and facilitated that of Ly6G+ granulocytic (G)-MDSCs more strongly than did rapamycin, G-MDSCs treated with rapamycin but not DON suppressed CD4+ T cell proliferation in vitro. The combination of rapamycin and DON significantly suppressed the arthritis in SKG mice more strongly than did each monotherapy in vivo. The numbers of CD4+ T and Th17 cells in the spleen were lowest in mice treated with the combination therapy. Thus, combined treatment with rapamycin and DON additively ameliorated the arthritis in SKG mice, possibly by suppressing CD4+ T cell proliferation and Th17 differentiation. These results suggest the combination of rapamycin and DON may be a potential novel therapy for arthritis.
Assuntos
Artrite/metabolismo , Glutamina/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Diazo-Oxo-Norleucina/farmacologia , Feminino , Terapia de Imunossupressão , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologiaRESUMO
Many alternative and complementary therapies for cancer have been reported. The objective of the present work is to examine antitumor and immune-modulatory properties of dual-treatment based on levamisole (Lms) and/or taurine (Tau) in Ehrlich ascites carcinoma-bearing mice. In the current study, Lms (10â¯mg/kg; subcutaneously) and Tau (640â¯mg/kg; intragastrically) was administered alone or as a dual-treatment. Lms or Tau was administered in combination with cyclophosphamide (CTX) (100â¯mg/kg; intraperitoneal) in mice bearing Ehrlich ascites carcinoma. Treatment with CTX or (Lms plus Tau) significantly reduced the ascitic tumor cell count, percentage of tumor cell viability while elevated the tumor inhibition rate and apoptosis percentage compared to non-treated animals. Dual-treatment (Lms and CTX) or (Tau and CTX) significantly potentiated the reduction of the ascitic tumor cell count, viability and augmented the tumor inhibition rate and apoptosis percentage compared to CTX-treated mice. Dual-treatment of (Lms plus Tau), (Lms plus CTX) or (Tau plus CTX) altered splenocytes immunological profile of CD3+CD4+, CD3+CD8+, CD4+CD25+ and CD11b+Ly6G+ cells in order to achieve better immune surveillance against tumor cells. In conclusion, dual-treatments based on Lms and/or Tau are promising therapies for cancer, not only due to its abilities to induce apoptosis in the tumor cells and modulate the immune response against them, but also due to its capabilities to potentiate the chemotherapy anticancer efficacy and minimize its adverse effects.