{"doi":"10.7302/6188","title":"Arginase 1 is a Key Driver of Immune Suppression and a Therapeutic Target of Pancreatic Cancer","abstract":"Pancreatic ductal adenocarcinoma (PDA) is the most common form of pancreatic cancer. PDA is a lethal disease with a 5-year survival rate of less than 11% after diagnosis. Some of the factors contributing to the aggressiveness and poor prognosis of this disease include late diagnosis (mostly due to non-specific or lack of symptoms), metastasis to other vital organs (mainly lungs and liver), lack of biomarkers for early screening, and resistance to current treatments. If outcomes do not improve, PDA is projected to become the second leading cause of cancer-related deaths by 2030. PDA is characterized by an abundant fibroinflammatory stroma mainly composed of fibroblasts and immune cells (notably macrophages). Infiltrating myeloid cells, mainly macrophages, express high levels of arginase 1 (ARG1), an enzyme that metabolizes L-arginine. In turn, L-arginine is required for CD8+ T cell activation and function. In contrast to myeloid cells, CD8+ T cells are rare in the pancreatic tumor microenvironment, and when present, they have an overwhelmingly exhausted phenotype. The goal of my thesis project was to investigate whether myeloid Arg1 drives immune suppression in PDA. I used a dual recombinase mouse model of PDA to delete Arg1 in myeloid cells and a pharmacological approach to inhibit arginase systemically in a syngeneic orthotopic implantation mouse model. In the genetic model, I observed decrease progression to invasive disease and macrophage repolarization. In the implantation model, I observed sensitization to anti-PD1 immune checkpoint treatment and reduced tumor growth upon treatment with the arginase inhibitor, CB-1158. In both settings, changes in tumor growth were accompanied by an increase in CD8+ T cell infiltration and activation. These results reveal that myeloid Arg1 is a mediator of immune suppression in PDA and could be therapeutically targeted to suppress tumor growth.","journal":"Deep Blue (University of Michigan)","year":2022,"id":311205,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":623506,"name":"Rosa E. Menjivar","orcid":"0000-0003-1551-869X","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T00:33:28.480200Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}