The Significance of Arginase I Administration on the Survival of Mice Bearing NS-1 Myeloma Cells

Wang, Soo-Ray; Hou, Stephen; Wang, Amy; Chang, Yu-Jun; Liu, Cheng-Tzu; Tsay, Gregory J.; Wei, James Cheng‐Chung

doi:10.1016/j.jss.2007.12.771

Cited by 5 publications

(5 citation statements)

References 16 publications

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“…Murine splenic NK cell cytotoxicity in a myeloma tumor model is also impaired by i.v. arginase injection, correlating with a shorter survival of the mice (42). Based on the data in our present study, we hypothesize that arginase within the tumor microenvironment, either myeloid cell-associated (28), passively liberated during PMN cell death (12), or by active secretion (43), suppresses the human antitumor NK cell response by inhibition of NK cell IFN-␥ secretion and proliferation.…”

Section: Discussionsupporting

confidence: 68%

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Regulation of NK Cell Function by Human Granulocyte Arginase

Oberlies

Watzl

Giese

et al. 2009

The Journal of Immunology

115

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The arginine-hydrolyzing enzyme arginase is constitutively expressed by human polymorphonuclear granulocytes (PMN). Upon PMN cell death arginase is liberated and depletes arginine in the microenvironment. This amino acid depletion suppresses T cell proliferation and cytokine secretion and emerges as a key mechanism of immunosuppression during chronic inflammation and tumor growth. Here we show that PMN arginase also severely impairs key functions of primary human NK cells as well as IL-2-activated NK cells. In the absence of arginine, NK cell proliferation and IL-12/IL-18-induced secretion of IFN-γ are severely diminished. In contrast, NK cell viability, granule exocytosis, and cytotoxicity are independent of extracellular arginine. The mechanism of NK cell suppression by arginine depletion is posttranscriptional since mRNA transcript frequency is unaffected upon NK cell activation in the absence of arginine. Finally, we demonstrate that human purulent exudate ex vivo inhibits NK cell functions exclusively due to liberated arginase. Arginase inhibitors are therefore promising pharmacological agents to treat unwanted suppression of the innate (NK cell) as well as the adaptive (T cell) immune system.

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Section: Discussionsupporting

confidence: 68%

“…4B) is in contrast to earlier studies that showed partial inhibition of NK cell-mediated killing upon arginine depletion (42,44). Similarly, cytotoxicity of naive or PHA-activated splenocytes was inhibited in arginase-preincubated medium (45).…”

Section: Discussionmentioning

confidence: 65%

Regulation of NK Cell Function by Human Granulocyte Arginase

Oberlies

Watzl

Giese

et al. 2009

The Journal of Immunology

115

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“…A study in syngeneic MM model indicated that ARG1 might play a role in suppressing antitumor immune response—intraperitoneal (i.p.) administration of recombinant ARG1 into mice with NS-1 MM significantly shortened the survival of tumor-bearing animals and impaired NK cells activity 17 . Moreover, bortezomib treatment was associated with increased serum ARG1 levels in MM patients and was suggested to contribute to treatment resistance 18 .…”

Section: Introductionmentioning

confidence: 94%

Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity

Ramji

Grzywa²,

Sosnowska³

et al. 2022

Sci Rep

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Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors.

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“…Recientemente Gannon y colaboradores (2010) reportaron que el uso de andrógenos induce la expresión de ARG1 y ARG2 en líneas celulares derivadas de cáncer de próstata. También se ha demostrado que la terapia antiandrogénica reduce la expresión in vitro de ARG2 en el tumor primario de pacientes con este tipo de neoplasia (46). Se ha encontrado la arginasa modulando la función del linfocito T por agotamiento del sustrato; en un modelo murino de trasplante de aloinjerto corneal, la inhibición de la arginasa in vivo aceleró el rechazo y en pequeñas dosis permitió la supervivencia de la piel en el trasplantado; es así como en la inmunología del trasplante de córnea la arginasa tiene un papel en la prevención del rechazo y posiblemente este efecto podría observarse en otros aloinjertos (44).…”

Section: Perspectivas Clínicas Y Aplicacionesunclassified

“…Las concentraciones de arginina, ARG y ONS en la sangre periférica o los tejidos tumorales han mostrado tener relevancia clínica en cuanto a la progresión tumoral, el pronóstico y la supervivencia de pacientes con cáncer (46). Se proponen estos indicadores como una estrategia de seguimiento terapéutico (27).…”

Section: Perspectivas Clínicas Y Aplicacionesunclassified

Arginina y cáncer: implicaciones en la regulación de la respuesta antitumoral

Correa

Gutiérrez

Lopera

2013

Iatreia

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Los informes de la literatura apoyan el papel de la arginina como mecanismo regulador de la respuesta inmune. Se ha descrito la correlación entre disminución de la arginina y reducción de la proliferación y la activación de los linfocitos T en trasplante hepático, trauma grave, sepsis y cáncer. Entre los efectos se describen la disminución en la expresión de la cadena CD3z (traducción de la señal de activación en el linfocito T). La disminución de la arginina está relacionada con la producción de arginasa 1 (ARG1) por parte de las células mieloides supresoras. Se han propuesto dos posibles mecanismos por medio de los cuales el aumento de la actividad de ARG1 podría estar actuando en un proceso tumoral. El primero es la disminución de la proliferación de los linfocitos y el freno del ciclo celular. El segundo es promover el crecimiento tumoral al transformar la arginina en precursores de poliaminas. Se presentan en este artículo los principales conceptos del papel de la arginina en la respuesta antitumoral.

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The Significance of Arginase I Administration on the Survival of Mice Bearing NS-1 Myeloma Cells

Cited by 5 publications

References 16 publications

Regulation of NK Cell Function by Human Granulocyte Arginase

Regulation of NK Cell Function by Human Granulocyte Arginase

Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity

Arginina y cáncer: implicaciones en la regulación de la respuesta antitumoral

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