Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity

Juan J. Miret, Paul Kirschmeier, Shohei Koyama, Mingrui Zhu, Yvonne Y. Li, Yujiro Naito, Min Wu, Venkat S. Malladi, Wei Huang, William Walker, Sangeetha Palakurthi, Glenn Dranoff, Peter S. Hammerman, Chad V. Pecot, Kwok Kin Wong, Esra Akbay

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Tumor orchestrated metabolic changes in the microenvironment limit generation of anti-tumor immune responses. Availability of arginine, a semi-essential amino acid, is critical for lymphocyte proliferation and function. Levels of arginine are regulated by the enzymes arginase 1,2 and nitric oxide synthase (NOS). However, the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant orthotopic tumor models. Methods: RNA sequencing (RNA-seq) of sorted cell populations from mouse lung adenocarcinomas derived from immunocompetent genetically engineered mouse models (GEMM)s was performed. To complement mouse studies, a patient tissue microarray consisting of 150 lung adenocarcinomas, 103 squamous tumors, and 54 matched normal tissue were stained for arginase, CD3, and CD66b by multiplex immunohistochemistry. Efficacy of a novel arginase inhibitor compound 9 in reversing arginase mediated T cell suppression was determined in splenocyte ex vivo assays. Additionally, the anti-tumor activity of this compound was determined in vitro and in an autochthonous immunocompetent Kras G12D GEMM of lung adenocarcinoma model. Results: Analysis of RNA-seq of sorted myeloid cells suggested that arginase expression is elevated in myeloid cells in the tumor as compared to the normal lung tissue. Accordingly, in the patient samples arginase 1 expression was mainly localized in the granulocytic myeloid cells and significantly elevated in both lung adenocarcinoma and squamous tumors as compared to the controls. Our ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSC)s cause T cell suppression by arginine depletion, and suppression of arginase activity by a novel ARG1/2 inhibitor, compound 9, led to restoration of T cell function by increasing arginine. Treatment of Kras G12D GEMM of lung cancer model with compound 9 led to a significant tumor regression associated with increased T cell numbers and function, while it had no activity across several murine and human non-small cell (NSCLC) lung cancer lines in vitro. Conclusions: We show that arginase expression is elevated in mouse and patient lung tumors. In a KRAS G12D GEMM arginase inhibition diminished growth of established tumors. Our data suggest arginase as an immunomodulatory target that should further be investigated in lung tumors with high arginase activity.

Original languageEnglish (US)
Article number504
JournalJournal for ImmunoTherapy of Cancer
Volume7
Issue number1
DOIs
StatePublished - Feb 6 2019

Fingerprint

Arginase
Myeloid Cells
Immunity
Neoplasms
Arginine
Therapeutics
RNA Sequence Analysis
T-Lymphocytes
Lung
Essential Amino Acids
Non-Small Cell Lung Carcinoma
Nitric Oxide Synthase
Lung Neoplasms

Keywords

  • Aminoacid
  • Arginase
  • Arginine
  • Autochthonous
  • Immunocompetent
  • MDSC
  • Metabolic checkpoint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity. / Miret, Juan J.; Kirschmeier, Paul; Koyama, Shohei; Zhu, Mingrui; Li, Yvonne Y.; Naito, Yujiro; Wu, Min; Malladi, Venkat S.; Huang, Wei; Walker, William; Palakurthi, Sangeetha; Dranoff, Glenn; Hammerman, Peter S.; Pecot, Chad V.; Wong, Kwok Kin; Akbay, Esra.

In: Journal for ImmunoTherapy of Cancer, Vol. 7, No. 1, 504, 06.02.2019.

Research output: Contribution to journalArticle

Miret, JJ, Kirschmeier, P, Koyama, S, Zhu, M, Li, YY, Naito, Y, Wu, M, Malladi, VS, Huang, W, Walker, W, Palakurthi, S, Dranoff, G, Hammerman, PS, Pecot, CV, Wong, KK & Akbay, E 2019, 'Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity', Journal for ImmunoTherapy of Cancer, vol. 7, no. 1, 504. https://doi.org/10.1186/s40425-019-0504-5
Miret, Juan J. ; Kirschmeier, Paul ; Koyama, Shohei ; Zhu, Mingrui ; Li, Yvonne Y. ; Naito, Yujiro ; Wu, Min ; Malladi, Venkat S. ; Huang, Wei ; Walker, William ; Palakurthi, Sangeetha ; Dranoff, Glenn ; Hammerman, Peter S. ; Pecot, Chad V. ; Wong, Kwok Kin ; Akbay, Esra. / Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity. In: Journal for ImmunoTherapy of Cancer. 2019 ; Vol. 7, No. 1.
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abstract = "Background: Tumor orchestrated metabolic changes in the microenvironment limit generation of anti-tumor immune responses. Availability of arginine, a semi-essential amino acid, is critical for lymphocyte proliferation and function. Levels of arginine are regulated by the enzymes arginase 1,2 and nitric oxide synthase (NOS). However, the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant orthotopic tumor models. Methods: RNA sequencing (RNA-seq) of sorted cell populations from mouse lung adenocarcinomas derived from immunocompetent genetically engineered mouse models (GEMM)s was performed. To complement mouse studies, a patient tissue microarray consisting of 150 lung adenocarcinomas, 103 squamous tumors, and 54 matched normal tissue were stained for arginase, CD3, and CD66b by multiplex immunohistochemistry. Efficacy of a novel arginase inhibitor compound 9 in reversing arginase mediated T cell suppression was determined in splenocyte ex vivo assays. Additionally, the anti-tumor activity of this compound was determined in vitro and in an autochthonous immunocompetent Kras G12D GEMM of lung adenocarcinoma model. Results: Analysis of RNA-seq of sorted myeloid cells suggested that arginase expression is elevated in myeloid cells in the tumor as compared to the normal lung tissue. Accordingly, in the patient samples arginase 1 expression was mainly localized in the granulocytic myeloid cells and significantly elevated in both lung adenocarcinoma and squamous tumors as compared to the controls. Our ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSC)s cause T cell suppression by arginine depletion, and suppression of arginase activity by a novel ARG1/2 inhibitor, compound 9, led to restoration of T cell function by increasing arginine. Treatment of Kras G12D GEMM of lung cancer model with compound 9 led to a significant tumor regression associated with increased T cell numbers and function, while it had no activity across several murine and human non-small cell (NSCLC) lung cancer lines in vitro. Conclusions: We show that arginase expression is elevated in mouse and patient lung tumors. In a KRAS G12D GEMM arginase inhibition diminished growth of established tumors. Our data suggest arginase as an immunomodulatory target that should further be investigated in lung tumors with high arginase activity.",
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T1 - Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity

AU - Miret, Juan J.

AU - Kirschmeier, Paul

AU - Koyama, Shohei

AU - Zhu, Mingrui

AU - Li, Yvonne Y.

AU - Naito, Yujiro

AU - Wu, Min

AU - Malladi, Venkat S.

AU - Huang, Wei

AU - Walker, William

AU - Palakurthi, Sangeetha

AU - Dranoff, Glenn

AU - Hammerman, Peter S.

AU - Pecot, Chad V.

AU - Wong, Kwok Kin

AU - Akbay, Esra

PY - 2019/2/6

Y1 - 2019/2/6

N2 - Background: Tumor orchestrated metabolic changes in the microenvironment limit generation of anti-tumor immune responses. Availability of arginine, a semi-essential amino acid, is critical for lymphocyte proliferation and function. Levels of arginine are regulated by the enzymes arginase 1,2 and nitric oxide synthase (NOS). However, the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant orthotopic tumor models. Methods: RNA sequencing (RNA-seq) of sorted cell populations from mouse lung adenocarcinomas derived from immunocompetent genetically engineered mouse models (GEMM)s was performed. To complement mouse studies, a patient tissue microarray consisting of 150 lung adenocarcinomas, 103 squamous tumors, and 54 matched normal tissue were stained for arginase, CD3, and CD66b by multiplex immunohistochemistry. Efficacy of a novel arginase inhibitor compound 9 in reversing arginase mediated T cell suppression was determined in splenocyte ex vivo assays. Additionally, the anti-tumor activity of this compound was determined in vitro and in an autochthonous immunocompetent Kras G12D GEMM of lung adenocarcinoma model. Results: Analysis of RNA-seq of sorted myeloid cells suggested that arginase expression is elevated in myeloid cells in the tumor as compared to the normal lung tissue. Accordingly, in the patient samples arginase 1 expression was mainly localized in the granulocytic myeloid cells and significantly elevated in both lung adenocarcinoma and squamous tumors as compared to the controls. Our ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSC)s cause T cell suppression by arginine depletion, and suppression of arginase activity by a novel ARG1/2 inhibitor, compound 9, led to restoration of T cell function by increasing arginine. Treatment of Kras G12D GEMM of lung cancer model with compound 9 led to a significant tumor regression associated with increased T cell numbers and function, while it had no activity across several murine and human non-small cell (NSCLC) lung cancer lines in vitro. Conclusions: We show that arginase expression is elevated in mouse and patient lung tumors. In a KRAS G12D GEMM arginase inhibition diminished growth of established tumors. Our data suggest arginase as an immunomodulatory target that should further be investigated in lung tumors with high arginase activity.

AB - Background: Tumor orchestrated metabolic changes in the microenvironment limit generation of anti-tumor immune responses. Availability of arginine, a semi-essential amino acid, is critical for lymphocyte proliferation and function. Levels of arginine are regulated by the enzymes arginase 1,2 and nitric oxide synthase (NOS). However, the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant orthotopic tumor models. Methods: RNA sequencing (RNA-seq) of sorted cell populations from mouse lung adenocarcinomas derived from immunocompetent genetically engineered mouse models (GEMM)s was performed. To complement mouse studies, a patient tissue microarray consisting of 150 lung adenocarcinomas, 103 squamous tumors, and 54 matched normal tissue were stained for arginase, CD3, and CD66b by multiplex immunohistochemistry. Efficacy of a novel arginase inhibitor compound 9 in reversing arginase mediated T cell suppression was determined in splenocyte ex vivo assays. Additionally, the anti-tumor activity of this compound was determined in vitro and in an autochthonous immunocompetent Kras G12D GEMM of lung adenocarcinoma model. Results: Analysis of RNA-seq of sorted myeloid cells suggested that arginase expression is elevated in myeloid cells in the tumor as compared to the normal lung tissue. Accordingly, in the patient samples arginase 1 expression was mainly localized in the granulocytic myeloid cells and significantly elevated in both lung adenocarcinoma and squamous tumors as compared to the controls. Our ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSC)s cause T cell suppression by arginine depletion, and suppression of arginase activity by a novel ARG1/2 inhibitor, compound 9, led to restoration of T cell function by increasing arginine. Treatment of Kras G12D GEMM of lung cancer model with compound 9 led to a significant tumor regression associated with increased T cell numbers and function, while it had no activity across several murine and human non-small cell (NSCLC) lung cancer lines in vitro. Conclusions: We show that arginase expression is elevated in mouse and patient lung tumors. In a KRAS G12D GEMM arginase inhibition diminished growth of established tumors. Our data suggest arginase as an immunomodulatory target that should further be investigated in lung tumors with high arginase activity.

KW - Aminoacid

KW - Arginase

KW - Arginine

KW - Autochthonous

KW - Immunocompetent

KW - MDSC

KW - Metabolic checkpoint

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