Immunosuppression in cervical cancer with special reference to arginase activity

Bedoya, Astrid Milena; Tate, David J.; Baena, Armando; Córdoba, C.; Borrero, Mauricio; Pareja, René; Rojas, Fredy; Patterson, John R.; Herrero, Rolando; Zea, Arnold H.; Sánchez, Gloria Inés

doi:10.1016/j.ygyno.2014.07.096

Cited by 24 publications

(13 citation statements)

References 35 publications

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“…ARG1 is a cytosolic protein, while ARG2 is mainly localized in the mitochondria 20 . High arginase levels, either ARG1 or ARG2, have been reported in several cancer types, including breast cancer 21 , NSCLC 22 , head and neck squamous cell carcinoma 23 , renal carcinoma 24 , colorectal cancer 25 , skin cancer 26 , and cervical cancer 27 . Arginases are mainly produced by myeloid-derived suppressor cells (MDSCs) that are highly enriched in the TME, and the role of ARG1-expressing MDSCs in altering T-cell responses in patients with cancer has been well established 28 .…”

Section: Introductionmentioning

confidence: 99%

Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma

et al. 2019

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Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1. EVs suppress proliferation of CD4 + and CD8 + T-cells in vitro and in vivo in OvCa mouse models. In mice, ARG1-containing EVs are transported to draining lymph nodes, taken up by dendritic cells and inhibit antigen-specific T-cell proliferation. Increased expression of ARG1 in mouse OvCa cells is associated with accelerated tumor progression that can be blocked by an arginase inhibitor. Altogether, our studies show that tumor cells use EVs as vehicles to carry over long distances and deliver to immune cells a metabolic checkpoint molecule – ARG1, mitigating anti-tumor immune responses.

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Section: Introductionmentioning

confidence: 99%

Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma

et al. 2019

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“…7 Increased expression of arginases (either Arg1 or Arg2) is perceived as a poor prognostic factor in a variety of cancer types including lung cancer, 8 head and neck cancer, 9 neuroblastoma, 10 acute myeloid leukemia, 11 pancreatic ductal carcinoma, 12 ovarian carcinoma, 13 or colorectal cancer. 14 Additionally, increased Arg activity was found in skin, 15 cervical, 16 thyroid follicular, 17 thyroid papillary and follicular variant of papillary, 17 gastric, bile duct, 18 hepatocellular, 19 breast 20 and esophageal 21 cancers, although the clear impact of increased Arg activity on patients' prognosis has not been reported in these tumor types. There are also ʟ-arg auxotrophic tumors such as melanoma 22 and renal carcinoma, 23,24 where no correlations between ʟ-arg concentrations and survival have been found.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

et al. 2021

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Immunotherapy has demonstrated significant activity in a broad range of cancer types, but still the majority of patients receiving it do not maintain durable therapeutic responses. Amino acid metabolism has been proposed to be involved in the regulation of immune response. Here, we investigated in detail the role of arginase 1 (Arg1) in the modulation of antitumor immune response against poorly immunogenic Lewis lung carcinoma. We observed that tumor progression is associated with an incremental increase in the number of Arg1 + myeloid cells that accumulate in the tumor microenvironment and cause systemic depletion of ʟ-arginine. In advanced tumors, the systemic concentrations of ʟ-arginine are decreased to levels that impair the proliferation of antigen-specific T-cells. Systemic or myeloid-specific Arg1 deletion improves antigen-induced proliferation of adoptively transferred T-cells and leads to inhibition of tumor growth. Arginase inhibitor was demonstrated to modestly inhibit tumor growth when used alone, and to potentiate antitumor effects of anti-PD-1 monoclonal antibodies and STING agonist. The effectiveness of the combination immunotherapy was insufficient to induce complete antitumor responses, but was significantly better than treatment with the checkpoint inhibitor alone. Together, these results indicate that arginase inhibition alone is of modest therapeutic benefit in poorly immunogenic tumors; however, in combination with other treatment strategies it may significantly improve survival outcomes.

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“…In a previous study, ARG2-expressing CAFs were associated with greater infiltration of CD68-positive macrophages and neutrophils but with lower infiltration of CD4+ and CD8+ T cells, indicating an immunosuppressive microenvironment [7]. The ARG-associated immunosuppression has also been reported recently by others [18]. As HCMV like other viruses is prone to be controlled by T-cell mediated immune response, the ‘ARG2-created immunosuppressive’ environment will thus favor virus survival.…”

Section: Resultsmentioning

confidence: 61%

Human cytomegalovirus may promote tumour progression by upregulating arginase-2

Costa

Overbeek

et al. 2016

Oncotarget

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BackgroundBoth arginase (ARG2) and human cytomegalovirus (HCMV) have been implicated in tumorigenesis. However, the role of ARG2 in the pathogenesis of glioblastoma (GBM) and the HCMV effects on ARG2 are unknown. We hypothesize that HCMV may contribute to tumorigenesis by increasing ARG2 expression.ResultsARG2 promotes tumorigenesis by increasing cellular proliferation, migration, invasion and vasculogenic mimicry in GBM cells, at least in part due to overexpression of MMP2/9. The nor-NOHA significantly reduced migration and tube formation of ARG2-overexpressing cells. HCMV immediate-early proteins (IE1/2) or its downstream pathways upregulated the expression of ARG2 in U-251 MG cells. Immunostaining of GBM tissue sections confirmed the overexpression of ARG2, consistent with data from subsets of Gene Expression Omnibus. Moreover, higher levels of ARG2 expression tended to be associated with poorer survival in GBM patient by analyzing data from TCGA.MethodsThe role of ARG2 in tumorigenesis was examined by proliferation-, migration-, invasion-, wound healing- and tube formation assays using an ARG2-overexpressing cell line and ARG inhibitor, N (omega)-hydroxy-nor-L-arginine (nor-NOHA) and siRNA against ARG2 coupled with functional assays measuring MMP2/9 activity, VEGF levels and nitric oxide synthase activity. Association between HCMV and ARG2 were examined in vitro with 3 different GBM cell lines, and ex vivo with immunostaining on GBM tissue sections. The viral mechanism mediating ARG2 induction was examined by siRNA approach. Correlation between ARG2 expression and patient survival was extrapolated from bioinformatics analysis on data from The Cancer Genome Atlas (TCGA).ConclusionsARG2 promotes tumorigenesis, and HCMV may contribute to GBM pathogenesis by upregulating ARG2.

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Immunosuppression in cervical cancer with special reference to arginase activity

Cited by 24 publications

References 35 publications

Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma

Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma

Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

Human cytomegalovirus may promote tumour progression by upregulating arginase-2

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