Arginase 1 is a key driver of immune suppression in pancreatic cancer
- University of Michigan-Ann Arbor, United States
- Henry Ford Pancreatic Cancer Center, United States
- University of California, Irvine, United States
Abstract
An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by expression of the enzyme Arginase 1 (Arg1), which we demonstrated is potently expressed in pancreatic tumor associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, Arg1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8+ T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8+ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting Arginine and inhibiting T cell activation.
Data availability
Human sc-RNA-seq data was previously published (N. G. Steele et al., 2020) and both raw and processed data are available at the NIH dbGap database accession number phs002071.v1.p1. Raw and processed sc-RNA-seq data for the WT and KPC were previously published and are available at GEO accession number GSM5011580 and GSE202651. Raw and processed sc-RNA-seq data for the KF and KFCA are available at GEO accession number GSE203016.
-
Arginase 1 deletion in myeloid cells decreases immune suppression and tumor formation in pancreatic cancerNCBI Gene Expression Omnibus, GSE203016.
-
Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic CancerNCBI Gene Expression Omnibus, GSE155698.
-
Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophagesNCBI Gene Expression Omnibus, GSM5011580.
-
Murine models of pancreatic cancer: KPCNCBI Gene Expression Omnibus, GSE202651.
Article and author information
Author details
Daniel Salas-Escabillas
Costas A Lyssiotis
Marina Pasca di Magliano
Funding
National Institutes of Health (T32-GM007315)
- Rosa Elena Menjivar
National Cancer Institute (R01-CA244931)
- Costas A Lyssiotis
National Cancer Institute (R01-CA247516)
- Howard C Crawford
University of Michigan (Postdoctoral Pioneer Program)
- Zeribe C Nwosu
University of Michigan (Training Program in Organogenesis)
- Wenting Du
National Cancer Institute (T32-CA009676)
- Katelyn L Donahue
National Cancer Institute (T32-AI007413)
- Hanna S Hong
National Institute of Diabetes and Digestive and Kidney Diseases (T32-DK094775)
- Hanna S Hong
National Cancer Institute (F31-CA247037)
- Ashley Velez-Delgado
National Institute of General Medical Sciences (T32-GM008353)
- Ashley Velez-Delgado
National Institutes of Health (T32-AI007413)
- Padma Kadiyala
National Cancer Institute (F31-CA257533)
- Rosa Elena Menjivar
National Cancer Institute (T32-CA009676)
- Daniel Salas-Escabillas
American College of Gastroenterology (T32-DK094775)
- Eileen Carpenter
National Cancer Institute (R50-CA232985)
- Yaqing Zhang
National Cancer Institute (F32-CA228328)
- Christopher J Halbrook
National Institutes of Health (R00-CA241357)
- Christopher J Halbrook
National Institutes of Health (T32-HD007505)
- Rosa Elena Menjivar
University of Michigan (Rackham Merit Fellowship)
- Rosa Elena Menjivar
National Institutes of Health (U01-CA224145)
- Marina Pasca di Magliano
National Institutes of Health (R01-CA151588)
- Marina Pasca di Magliano
National Cancer Institute (R01-CA198074)
- Marina Pasca di Magliano
National Cancer Institute (R37-CA237421)
- Costas A Lyssiotis
National Cancer Institute (R01-CA248160)
- Costas A Lyssiotis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All the animal studies and procedures were conducted in compliance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) at the University of Michigan, protocol number: PRO00009814.
Human subjects: Human research was performed in accordance with the Declaration of Helsinki and the ethical standards and guidelines approved by the University of Michigan Institutional Review Board. Patients provided written informed consent.
Copyright
© 2023, Menjivar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,714
- views
-
- 899
- downloads
-
- 56
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Arginase 1 is a key driver of immune suppression in pancreatic cancer
eLife 12:e80721.
https://doi.org/10.7554/eLife.80721
Further reading
-
- Biochemistry and Chemical Biology
- Cancer Biology
Studying the nutrient composition immediately surrounding pancreatic cancer cells provides new insights into their metabolic properties and how they can evade the immune system to promote disease progression.
-
- Cancer Biology
- Chromosomes and Gene Expression
Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high-throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD in human cells. This screen implicated disruption of kinase SMG1’s phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from human and murine truncating mutations in vitro and murine cells in vivo. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable human leukocyte antigens (HLA) class I-associated peptides from NMD-downregulated proteins on the surface of human cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.
