Boronic acid-based arginase inhibitors in cancer immunotherapy

Borek, Bartłomiej; Gajda, Tadeusz; Gołębiowski, Adam; Błaszczyk, Roman

doi:10.1016/j.bmc.2020.115658

Cited by 28 publications

(29 citation statements)

References 66 publications

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“…These observations also suggest novel therapeutic approaches including the use of arginase inhibitors or the replenishment of arginine. Arg1 inhibitors are currently in early phase clinical trials in cancer (Calithera/Incyte (39,40)), while the replenishment of arginine or arginine precursors has been tested in sickle cell disease resulting in a significant reduction in vaso-occlusive complications (41,42). Arginine replenishment has also been tested in surgery where it successfully blunted the surge of G-MDSC, prevented T cell dysfunction and decreased infectious complications (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells

et al. 2021

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COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.

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Section: Discussionmentioning

confidence: 99%

Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells

et al. 2021

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“…Several Arg inhibitors have been described so far, including both natural and synthetic compounds. 38,62,63 Almost all developed as drug candidates are competitive inhibitors of both isoenzymes (Arg1 and Arg2). Finding an isoform-specific Arg inhibitor is challenging due to extensive homology in the active site of the enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies in mice indicated that treatment with Arg inhibitors such as nor-NOHA or CB-1158 resulted in reduced tumor growth 28,37 indicating that Arg is a relevant therapeutic target. In this study, we investigated the role of Arg1 in the tumor microenvironment of lung carcinoma and test whether a novel Arg inhibitor 13,38 would be able to modulate antitumor immune response either alone or in combination with other immunotherapeutic approaches. The results obtained in this study confirm previous findings indicating increased infiltration of tumors with Arg1-producing myeloid cells and expand these observations by providing more detailed analysis of cell populations that lead to a systemic decrease in ʟ-arg concentrations.…”

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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“…These observations also suggest novel therapeutic approaches including the use of arginase inhibitors or the replenishment of arginine. Arg1 inhibitors are currently in early phase clinical trials in cancer (Calithera/Incyte; 31,32 ), while the replenishment of arginine or arginine precursors has been tested in Sickle cell disease resulting in a significant reduction in vaso-occlusive complications 33,34 Arginine replenishment has also been tested in surgery where it successfully blunted the surge of G-MDSC, prevented T cell dysfunction and decreased infectious complications [35][36][37] . Therefore arginase 1 inhibition and/or arginine replenishment should be considered as an adjuvant to the prevention/treatment of COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome and Functions of Granulocytic Myeloid-Derived Suppressor Cells Determine their Association with Disease Severity of COVID-19

Dean

Ochoa

Sanchez-Pino

et al. 2021

Preprint

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COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19, that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of Granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.

show abstract

Boronic acid-based arginase inhibitors in cancer immunotherapy

Cited by 28 publications

References 66 publications

Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells

Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells

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

Transcriptome and Functions of Granulocytic Myeloid-Derived Suppressor Cells Determine their Association with Disease Severity of COVID-19

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