RESUMO
Advances in human stem cell technologies enable induced pluripotent stem cells (iPSCs) to be explored as potent candidates for treating various diseases, such as malignancies, autoimmunity, immunodeficiencies, and allergic reactions. iPSCs with infinite self-renewal ability can be derived from different types of somatic cells without the ethical issues associated with embryonic stem cells. To date, numerous cell types, including various immune cell subsets [CD4+ and CD8+ T cells, gamma delta T (γδ T) cells, regulatory T cells, dendritic cells, natural killer cells, macrophages, and neutrophils] have successfully been generated from iPSCs paving the way for effective adoptive cell transfer therapy, drug development, and disease modeling. Herein, we review various iPSC-derived immune cells and their possible application in immunotherapy.
Assuntos
Diferenciação Celular , Imunoterapia Adotiva , Células-Tronco Pluripotentes Induzidas , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Imunoterapia Adotiva/métodos , Animais , Células Matadoras Naturais/imunologiaRESUMO
Background: It is well-known that TH1 and Treg cells exert anti- and pro-tumorigenic activity, respectively. Thus, TH1 cell suppression together with Treg cell hyperactivation contribute to tumor development. Glycyrrhiza glabra (G. glabra) has various immunomodulatory and anti-tumorigenic properties. Objective: To explore the impacts of G. glabra extract on different parameters related to TH1 and Treg cells using a breast cancer (BC) model. Methods: Four groups of Balb/C mice bearing 4T1 cell-induced BC were treated intraperitoneally with either saline or G. glabra extract at dosages of 50, 100 and 150 mg/kg (G. glabra-50, G. glabra-100, and G. glabra-150, respectively). After sacrificing animals on day 26, the frequency of splenic TH1 and Treg cells, the levels of serum IFN-γ, TGF-ß, and IL-12, and intra-tumoral expressions of granzyme-B, T-bet, and FOXP3 were assessed. Results: Compared to untreated tumor control (UTC) group, treatment with G. glabra-50, G. glabra-100, or G. glabra-150 increased the survival rate, percentage of TH1 cells, and T-bet expression. Conversely, they reduced the percentage of Treg cells, and serum TGF-ß levels. In comparison to the UTC group, treatment with G. glabra-50 and G. glabra-150 increased the serum IL-12 levels. Treatment with G. glabra-100 and G. glabra-150 boosted granzyme-B expression. Treatment with G. glabra-150 elevated IFN-γ levels, while treatment with G. glabra-50 decreased the FOXP3 expression. IL-12 levels were higher in mice treated with G. glabra-150 compared to those treated with G. glabra-100. Conclusion: Treatment of mice with BC using G. glabra extract improved survival rate, reduced tumor growth, and modulated T cell-mediated immune responses.
Assuntos
Neoplasias da Mama , Modelos Animais de Doenças , Glycyrrhiza , Extratos Vegetais , Linfócitos T Reguladores , Células Th1 , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Feminino , Camundongos , Células Th1/imunologia , Células Th1/efeitos dos fármacos , Glycyrrhiza/química , Extratos Vegetais/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Humanos , Citocinas/metabolismo , Imunomodulação/efeitos dos fármacosRESUMO
PURPOSE: In dendritic cells (DCs), leptin as an immune-regulating hormone, increases the IL-12 generation whereas it reduces the IL-10 production, thus contributing to TH1 cell differentiation. Using a murine model of breast cancer (BC), we evaluated the impacts of the Leptin and/or lipopolysaccharide (LPS)-treated DC vaccine on various T-cell-related immunological markers. MATERIALS AND METHODS: Tumors were established in mice by subcutaneously injecting 7 × 105 4T1 cells into the right flank. Mice received the DC vaccines pretreated with Leptin, LPS, and both Leptin/LPS, on days 12 and 19 following tumor induction. The animals were sacrificed on day 26 and after that the frequency of the splenic cytotoxic T lymphocytes (CTLs) and TH1 cells; interferon gamma (IFN-γ), interleukin 12 (IL-12) and tumor growth factor beta (TGF-ß) generation by tumor lysate-stimulated spleen cells, and the mRNA expression of T-bet, FOXP3 and Granzyme B in the tumors were measured with flow cytometry, ELISA and real-time PCR methods, respectively. RESULTS: Leptin/LPS-treated mDC group was more efficient in blunting tumor growth (p = .0002), increasing survival rate (p = .001), and preventing metastasis in comparison with the untreated tumor-bearing mice (UT-control). In comparison to the UT-control group, treatment with Leptin/LPS-treated mDC also significantly increased the splenic frequencies of CTLs (p < .001) and TH1 cells (p < .01); promoted the production of IFN-γ (p < .0001) and IL-12 (p < .001) by splenocytes; enhanced the T-bet (p < .05) and Granzyme B (p < .001) expression, whereas decreased the TGF-ß and FOXP3 expression (p < .05). CONCLUSION: Compared to the Leptin-treated mDC and LPS-treated mDC vaccines, the Leptin/LPS-treated mDC vaccine was more effective in inhibiting BC development and boosting immune responses against tumor.
Assuntos
Neoplasias , Vacinas , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Granzimas/metabolismo , Leptina/metabolismo , Imunidade Celular , Fator de Crescimento Transformador beta/metabolismo , Interferon gama/metabolismo , Modelos Animais , Neoplasias/metabolismo , Interleucina-12 , Vacinas/metabolismo , Células Dendríticas , Fatores de Transcrição Forkhead/metabolismoRESUMO
PURPOSE: Prostaglandin E2 (PGE2), a product of cyclooxygenase (COX) pathway of arachidonic acid, exerts inhibitory impacts on dendritic cell (DC) activity to repress anti-tumor immune responses. Therefore, targeting COX during DC vaccine generation may enhance DC-mediated antitumor responses. We aimed to investigate the impacts of DC vaccine treated with celecoxib (CXB), a selective COX2 inhibitor, on some T cell-related parameters. MATERIALS AND METHODS: Breast cancer (BC) was induced in BALB/c mice, and then they received DC vaccine treated with lipopolysaccharide (LPS-mDCs), LPS with a 5 âµM dose of CXB (LPS/CXB5-mDCs) and LPS with a 10 âµM dose of CXB (LPS/CXB10-mDCs). The frequency of splenic Th1 and Treg cells and amounts of IFN-γ, IL-12 and TGF-ß production by splenocytes, as well as, the expression of Granzyme-B, T-bet and FOXP3 in tumors were determined using flow cytometry, ELISA, and real-time PCR, respectively. RESULTS: Compared with untreated tumor group (T-control), treatment with LPS/CXB5-mDCs and LPS/CXB10-mDCs decreased tumor growth (P â= â0.009 and P â< â0.0001), escalated survival rate (P â= â0.002), increased the frequency of splenic Th1 cells (P â= â0.0872, and P â= â0.0155), increased the IFN-γ (P â= â0.0003 and P â= â0.0061) and IL-12 (P â= â0.001 and P â= â0.0009) production by splenocytes, upregulated T-bet (P â= â0.062 and P â< â0.0001) and Granzyme-B (P â= â0.0448 and P â= â0.4485), whereas decreased the number of Treg cells (P â= â0.0014, and P â= â0.0219), reduced the amounts of TGF-ß production by splenocytes (P â= â0.0535 and P â= â0.0169), and reduced the expression of FOXP3 (P â= â0.0006 and P â= â0.0057) in comparison with T-control group. CONCLUSIONS: Our findings show that LPS/CXB-treated DC vaccine potently modulated antitumor immune responses in a mouse BC model.