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1.
Front Immunol ; 11: 1820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013832

RESUMO

Galectin-3 (Gal-3) is an extracellular matrix glycan-binding protein with several immunosuppressive and pro-tumor functions. The role of Galectin-3 in cancer stem-like cells (CSCs) is poorly investigated. Here, we show that prostate CSCs also colonizing prostate-draining lymph nodes of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice overexpress Gal-3. Gal-3 contributes to prostate CSC-mediated immune suppression because either Gal-3 silencing in CSCs, or co-culture of CSCs and T cells in the presence of the Gal-3 inhibitor N-Acetyl-D-lactosamine rescued T cell proliferation. N-Acetyl-D-lactosamine also rescued the proliferation of T cells in prostate-draining lymph nodes of TRAMP mice affected by prostate intraepithelial neoplasia. Additionally, Gal-3 impacted prostate CSC tumorigenic and metastatic potential in vivo, as Gal-3 silencing in prostate CSCs reduced both primary tumor growth and secondary invasion. Gal-3 was also found expressed in more differentiated prostate cancer cells, but with different intracellular distribution as compared to CSCs, which suggests different functions of Gal-3 in the two cell populations. In fact, the prevalent nuclear and cytoplasmic distribution of Gal-3 in prostate CSCs made them less susceptible to apoptosis, when compared to more differentiated prostate cancer cells, in which Gal-3 was predominantly intra-cytoplasmic. Finally, we found Gal-3 expressed in human and mouse prostate intraepithelial neoplasia lesions and in metastatic lymph nodes. All together, these findings identify Gal-3 as a key molecule and a potential therapeutic target already in the early phases of prostate cancer progression and metastasis.


Assuntos
Adenocarcinoma/metabolismo , Galectina 3/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasias da Próstata/metabolismo , Evasão Tumoral , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/secundário , Animais , Proteínas Sanguíneas , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Galectina 3/genética , Galectinas , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neoplásicas/imunologia , Neoplasia Prostática Intraepitelial/genética , Neoplasia Prostática Intraepitelial/imunologia , Neoplasia Prostática Intraepitelial/secundário , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Transdução de Sinais , Microambiente Tumoral
2.
Cancer Res ; 77(3): 658-671, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27872095

RESUMO

Donor-derived allogeneic T cells evoke potent graft versus tumor (GVT) effects likely due to the simultaneous recognition of tumor-specific and host-restricted minor histocompatibility (H) antigens. Here we investigated whether such effects could be reproduced in autologous settings by TCR gene-engineered lymphocytes. We report that T cells redirected either to a broadly expressed Y-encoded minor H antigen or to a tumor-associated antigen, although poorly effective if individually transferred, when simultaneously administered enabled acute autochthonous tumor debulking and resulted in durable clinical remission. Y-redirected T cells proved hyporesponsive in peripheral lymphoid organs, whereas they retained effector function at the tumor site, where in synergy with tumor-redirected lymphocytes, they instructed TNFα expression, endothelial cell activation, and intratumoral T-cell infiltration. While neutralizing TNFα hindered GVT effects by the combined T-cell infusion, a single injection of picogram amounts of NGR-TNF, a tumor vessel-targeted TNFα derivative currently in phase III clinical trials, substituted for Y-redirected cells and enabled tumor debulking by tumor-redirected lymphocytes. Together, our results provide new mechanistic insights into allogeneic GVT, validate the importance of targeting the tumor and its associated stroma, and prove the potency of a novel combined approach suitable for immediate clinical implementation. Cancer Res; 77(3); 658-71. ©2016 AACR.


Assuntos
Adenocarcinoma/patologia , Linfócitos T CD8-Positivos/transplante , Imunoterapia Adotiva/métodos , Antígenos de Histocompatibilidade Menor/imunologia , Neoplasias da Próstata/patologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Linfócitos T CD8-Positivos/imunologia , Citometria de Fluxo , Imunofluorescência , Perfilação da Expressão Gênica , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real
3.
Hum Gene Ther ; 26(4): 220-31, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25758764

RESUMO

Cytokine-induced killer (CIK) cells consist of a heterogeneous population of polyclonal T lymphocytes displaying NK phenotype and HLA-unrestricted cytotoxic activity against a broad range of tumors. We sought to determine whether transduction of CIK cells with T cell receptor (TCR) genes specific for tumor-associated antigens could generate effector cells endowed with a double mechanism of tumor recognition. HLA-A2-restricted TCR-transduced (TD) CIK directed against the melanoma antigens Mart1 and NY-ESO1 were generated by lentiviral transduction and successfully expanded over a 3-4-week period. TD-CIK cells were both CD3(+)/CD56(-) and CD3(+)/CD56(+) (31±8% and 59±9%, respectively), indicating that both major histocompatibility complex (MHC)-restricted T cells and MHC-unrestricted CIK could be targeted by lentiviral transduction. At the end of the culture, the majority of both unmodified and TD-CIK displayed an effector memory phenotype, without considerable expression of replicative senescence and exhaustion markers. Functionally, TD-CIK specifically recognized tumor cells expressing the relevant antigen as well as maintained their MHC-unrestricted tumor activity. The cytotoxic activity of TD-CIK against HLA-A2(+) melanoma cell lines was significantly higher than the untransduced counterparts at a low effector:target ratio (cytotoxic activity of TD-CIK was from 1.9- to 4.3-fold higher than untransduced counterparts). TD-CIK were highly proficient in releasing high amount of IFN-γ upon antigen-specific stimulation and were able to recognize primary melanoma targets. In conclusion, we showed that (1) the reproducibility and simplicity of CIK transduction and expansion might solve the problem of obtaining adequate numbers of potent antitumor effector cells for adoptive immunotherapy; (2) the presence of both terminal effectors as well as of less differentiated progenitors might confer them long survival in vivo; and (3) the addition of an MHC-restricted antigen recognition allows not only targeting tumor surface antigens but also a wider range of cytoplasmic or nuclear antigens, involved in tumor proliferation and survival. TD-CIK cells with a double mechanism of tumor recognition are an attractive and alternative tool for the development of efficient cell therapeutic strategies.


Assuntos
Subpopulações de Linfócitos B/imunologia , Citocinas/fisiologia , Melanoma/terapia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/biossíntese , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Engenharia Genética , Humanos , Imunoterapia Adotiva , Leucócitos Mononucleares/imunologia , Melanoma/imunologia , Receptores de Antígenos de Linfócitos T/genética
4.
J Immunol ; 177(9): 6143-51, 2006 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17056542

RESUMO

Dendritic cells (DCs) are indispensable for initiation of primary T cell responses and a host's defense against infection. Many proinflammatory stimuli induce DCs to mature (mDCs), but little is known about the ability of chemokines to modulate their maturation. In the present study, we report that CCL16 is a potent maturation factor for monocyte-derived DCs (MoDCs) through differential use of its four receptors and an indirect regulator of Th cell differentiation. MoDCs induced to mature by CCL16 are characterized by increased expression of CD80 and CD86, MHC class II molecules, and ex novo expression of CD83 and CCR7. They produce many chemokines to attract monocytes and T cells and are also strong stimulators in activating allogeneic T cells to skew toward Th1 differentiation. Interestingly, they are still able to take up Ag and express chemokine receptors usually bound by inflammatory ligands and can be induced to migrate to different sites where they capture Ags. Our findings indicate that induction of MoDC maturation is an important property of CCL16 and suggest that chemokines may not only organize the migration of MoDCs, but also directly regulate their ability to prime T cell responses.


Assuntos
Quimiocinas CC/farmacologia , Células Dendríticas/imunologia , Monócitos/imunologia , Antígenos CD/análise , Diferenciação Celular , Movimento Celular , Quimiocinas/metabolismo , Quimiocinas CC/fisiologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/análise , Humanos , Ligantes , Ativação Linfocitária , Monócitos/efeitos dos fármacos , Receptores CCR7 , Receptores de Quimiocinas/análise , Linfócitos T/imunologia
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