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

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

  • J Immunother Cancer. 2019 Feb 6;7(1):32. doi: 10.1186/s40425-019-0504-5.
Juan J Miret 1,  Paul Kirschmeier 1,  Shohei Koyama 2,  Mingrui Zhu 3 4,  Yvonne Y Li 5,  Yujiro Naito 2,  Min Wu 1,  Venkat S Malladi 6 7,  Wei Huang 1 8,  William Walker 1,  Sangeetha Palakurthi 1 8,  Glenn Dranoff 5 9,  Peter S Hammerman 5 9 10,  Chad V Pecot 11,  Kwok-Kin Wong 12,  Esra A Akbay 13 14
Affiliations

Affiliations

  • 1 Dana Farber Cancer Institute, Belfer Institute of Cancer Science, Boston, MA, USA.
  • 2 Department of Respiratory Medicine and Clinical Immunology, Graduate School of medicine, Osaka University, Osaka, Japan.
  • 3 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 4 Simmons Comprehensive Cancer Center, Esra Akbay, PhD, Address: 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.
  • 5 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
  • 6 Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 7 Bioinformatics Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 8 Elstar Therapeutics, Cambridge, MA, USA.
  • 9 Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • 10 Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 11 University of North Carolina Chapel Hill, Lineberger Cancer Center, Chapel Hill, NC, USA.
  • 12 Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
  • 13 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. esra.akbay@utsouthwestern.edu.
  • 14 Simmons Comprehensive Cancer Center, Esra Akbay, PhD, Address: 5323 Harry Hines Blvd, Dallas, TX, 75390, USA. esra.akbay@utsouthwestern.edu.
PMID: 30728077 DOI: 10.1186/s40425-019-0504-5
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 KrasG12D 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 KrasG12D 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 KRASG12D 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.

Keywords

Aminoacid; Arginase; Arginine; Autochthonous; Immunocompetent; MDSC; Metabolic checkpoint.

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