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1.
Nat Commun ; 15(1): 4701, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38830882

RESUMO

Immune checkpoint blockade (ICB) therapies function by alleviating immunosuppression on tumor-infiltrating lymphocytes (TILs) but are often insufficient to fully reactivate these dysfunctional TILs. Although interleukin 12 (IL-12) has been used in combination with ICB to improve efficacy, this remains limited by severe toxicity associated with systemic administration of this cytokine. Here, we engineer a fusion protein composed of an anti-PD-1 antibody and a mouse low-affinity IL-12 mutant-2 (αPD1-mIL12mut2). Systemic administration of αPD1-mIL12mut2 displays robust antitumor activities with undetectable toxicity. Mechanistically, αPD1-mIL12mut2 preferentially activates tumor-infiltrating PD-1+CD8+T cells via high-affinity αPD-1 mediated cis-binding of low-affinity IL-12. Additionally, αPD1-mIL12mut2 treatment exerts an abscopal effect to suppress distal tumors, as well as metastasis. Collectively, αPD1-mIL12mut2 treatment induces robust systemic antitumor responses with reduced side effects.


Assuntos
Linfócitos T CD8-Positivos , Interleucina-12 , Linfócitos do Interstício Tumoral , Receptor de Morte Celular Programada 1 , Animais , Interleucina-12/metabolismo , Interleucina-12/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Camundongos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Feminino , Inibidores de Checkpoint Imunológico/farmacologia , Humanos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética
2.
J Exp Med ; 219(12)2022 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-36165896

RESUMO

Checkpoint blockade immunotherapy releases the inhibition of tumor-infiltrating lymphocytes (TILs) but weakly induces TIL proliferation. Exogenous IL-15 could further expand TILs and thus synergize with αPD-L1 therapy. However, systemic delivery of IL-15 extensively expands peripheral NK cells, causing severe toxicity. To redirect IL-15 to intratumoral PD-1+CD8+T effector cells instead of NK cells for better tumor control and lower toxicity, we engineered an anti-PD-1 fusion with IL-15-IL-15Rα, whose activity was geographically concealed by immunoglobulin Fc region with an engineered linker (αPD-1-IL-15-R) to bypass systemic NK cells. Systematic administration of αPD-1-IL-15-R elicited extraordinary antitumor efficacy with undetectable toxicity. Mechanistically, cis-delivery of αPD-1-IL-15-R vastly expands tumor-specific CD8+T cells for tumor rejection. Additionally, αPD-1-IL-15-R upregulated PD-1 and IL-15Rß on T cells to create a feedforward activation loop, thus rejuvenating TILs, not only resulting in tumor control in situ, but also suppressing tumor metastasis. Collectively, renavigating IL-15 to tumor-specific PD-1+CD8+T cells, αPD-1-IL-15-R elicits effective systemic antitumor immunity.


Assuntos
Interleucina-15 , Neoplasias , Linfócitos T CD8-Positivos , Humanos , Inibidores de Checkpoint Imunológico , Interleucina-15/farmacologia , Linfócitos do Interstício Tumoral
3.
Sci Immunol ; 7(67): eabi6899, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34995098

RESUMO

It is a challenge to effectively reactivate preexisting tumor-infiltrating lymphocytes (TILs) without causing severe toxicity. Interleukin-12 (IL-12) can potently activate lymphocytes, but its clinical use is limited by its short half-life and dose-related toxicity. In this study, we developed a tumor-conditional IL-12 (pro-IL-12), which masked IL-12 with selective extracellular receptor­binding domains of the IL-12 receptor while preferentially and persistently activating TILs after being unmasked by matrix metalloproteinases expressed by tumors. Systemic delivery of pro-IL-12 demonstrated reduced toxicity but better control of established tumors compared with IL-12-Fc. Mechanistically, antitumor responses induced by pro-IL-12 were dependent on TILs and IFNγ. Furthermore, direct binding of IL-12 to IL-12R on CD8+, not CD4+, T cells was essential for maximal effectiveness. Pro-IL-12 improved the efficacy of both immune checkpoint blockade and targeted therapy when used in combination. Therefore, our study demonstrated that pro-IL-12 could rejuvenate TILs, which then combined with current treatment modalities while limiting adverse effects for treating established tumors.


Assuntos
Interleucina-12/imunologia , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
4.
Biochim Biophys Acta Mol Basis Dis ; 1864(5 Pt A): 1744-1753, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29499325

RESUMO

The transcriptional co-activator Yes-associated protein (YAP) has been implicated as an oncogene and is found to promote breast cancer metastasis. However, the pro-metastatic mechanism of YAP remains unclear. Here, we demonstrated that YAP functions as a transcriptional repressor of growth differentiation factor-15 (GDF15), a divergent member of the transforming growth factor superfamily, in several breast cancer cell lines. Functionally, knockdown of YAP decreased, whereas knockdown of GDF15 increased, the metastatic potential of breast cancer cells. More than that, the reduced metastasis in YAP-depleted cells could be reversed by simultaneous knockdown of GDF15. Mechanistically, the repressive effect of YAP on GDF15 requires its transcriptional factor TEAD (TEA domain family). In addition, YAP recruits polycomb repressive complex 2 (PRC2) to tri-methylate histone H3 lysine 27 in the promoter region of GDF15. Co-immunoprecipitation experiments demonstrated that YAP and enhancer of zeste 2 PRC2 subunit (EZH2) physically interact with each other. In conclusion, our data reveal that YAP promotes metastasis of breast cancer cells by repressing GDF15 transcription and present a novel molecular mechanism underlying the pro-metastasis function of YAP oncoprotein, with the implication of a therapeutic avenue for breast cancer treatment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator 15 de Diferenciação de Crescimento/biossíntese , Fosfoproteínas/metabolismo , Transcrição Gênica , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Camundongos , Metástase Neoplásica , Fosfoproteínas/genética , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Fatores de Transcrição , Proteínas de Sinalização YAP
5.
Yi Chuan ; 39(7): 675-682, 2017 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-28757481

RESUMO

The Hippo signaling pathway plays a critical role in body development and tissue growth. As the core effector of the Hippo signaling pathway, Yes-associated protein (YAP) has been reported to be involved in various kinds of human cancers. However, the mechanism for the regulation of YAP activity has not been completely understood. In this study, we constructed a YAP Thr425Ala mutant and found that this mutation decreased YAP transcriptional activity. Further, T425A retained YAP in the cytoplasm without affecting the phosphorylation of YAP S127. Moreover, we observed that the T425A mutation attenuated the ability of YAP in driving MCF10A cell migration. Our research indicates that T425 of YAP is important for the regulation of YAP localization and activity.


Assuntos
Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Proteínas de Ciclo Celular , Movimento Celular , Células HEK293 , Humanos , Células MCF-7 , Proteínas Nucleares/fisiologia , Fosforilação , Fatores de Transcrição/fisiologia
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