Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity
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...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2019-02-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0504-5 |
| _version_ | 1828861901157695488 |
|---|---|
| author | 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 A. Akbay |
| author_facet | 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 A. Akbay |
| author_sort | Juan J. Miret |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T03:11:49Z |
| format | Article |
| id | doaj.art-78dba48bba534719a4cc483ade3990dd |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-13T03:11:49Z |
| publishDate | 2019-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-78dba48bba534719a4cc483ade3990dd2022-12-22T00:01:34ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-02-017111210.1186/s40425-019-0504-5Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor ImmunityJuan J. Miret0Paul Kirschmeier1Shohei Koyama2Mingrui Zhu3Yvonne Y. Li4Yujiro Naito5Min Wu6Venkat S. Malladi7Wei Huang8William Walker9Sangeetha Palakurthi10Glenn Dranoff11Peter S. Hammerman12Chad V. Pecot13Kwok-Kin Wong14Esra A. Akbay15Dana Farber Cancer Institute, Belfer Institute of Cancer ScienceDana Farber Cancer Institute, Belfer Institute of Cancer ScienceDepartment of Respiratory Medicine and Clinical Immunology, Graduate School of medicine, Osaka UniversityDepartment of Pathology, University of Texas Southwestern Medical CenterDepartment of Medical Oncology, Dana Farber Cancer InstituteDepartment of Respiratory Medicine and Clinical Immunology, Graduate School of medicine, Osaka UniversityDana Farber Cancer Institute, Belfer Institute of Cancer ScienceDepartment of Bioinformatics, University of Texas Southwestern Medical CenterDana Farber Cancer Institute, Belfer Institute of Cancer ScienceDana Farber Cancer Institute, Belfer Institute of Cancer ScienceDana Farber Cancer Institute, Belfer Institute of Cancer ScienceDepartment of Medical Oncology, Dana Farber Cancer InstituteDepartment of Medical Oncology, Dana Farber Cancer InstituteUniversity of North Carolina Chapel Hill, Lineberger Cancer CenterLaura and Isaac Perlmutter Cancer Center, New York University Langone Medical CenterDepartment of Pathology, University of Texas Southwestern Medical CenterAbstract 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.http://link.springer.com/article/10.1186/s40425-019-0504-5ArginaseMDSCArginineMetabolic checkpointAminoacidImmunocompetent |
| spellingShingle | 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 A. Akbay 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 Arginase MDSC Arginine Metabolic checkpoint Aminoacid Immunocompetent |
| title | Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity |
| title_full | Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity |
| title_fullStr | Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity |
| title_full_unstemmed | Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity |
| title_short | Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity |
| title_sort | suppression of myeloid cell arginase activity leads to therapeutic response in a nsclc mouse model by activating anti tumor immunity |
| topic | Arginase MDSC Arginine Metabolic checkpoint Aminoacid Immunocompetent |
| url | http://link.springer.com/article/10.1186/s40425-019-0504-5 |
| work_keys_str_mv | AT juanjmiret suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT paulkirschmeier suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT shoheikoyama suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT mingruizhu suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT yvonneyli suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT yujironaito suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT minwu suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT venkatsmalladi suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT weihuang suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT williamwalker suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT sangeethapalakurthi suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT glenndranoff suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT petershammerman suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT chadvpecot suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT kwokkinwong suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity AT esraaakbay suppressionofmyeloidcellarginaseactivityleadstotherapeuticresponseinansclcmousemodelbyactivatingantitumorimmunity |