title: Expression of arginase I in myeloid cells limits control of residual disease after radiation therapy of tumors in mice.
abstract: An accumulating body of evidence demonstrates that radiation therapy can generate adaptive immune responses that contribute to tumor control. However, in the absence of additional immune therapy, the adaptive immune response is insufficient to prevent tumor recurrence or affect distant disease. It has been shown in multiple models that tumor-infiltrating myeloid cells exhibit alternative activation phenotypes and are able to suppress adaptive immune responses, and recent data suggests that the myeloid response in tumors treated with cytotoxic therapy limits tumor control. We hypothesized that tumor myeloid cells inhibit the adaptive immune response after radiation therapy through expression of the enzyme arginase I. Using a myeloid cell-specific deletion of arginase I in mice, we demonstrate an improved tumor control after radiation therapy. However, tumors still recurred despite the conditional knockdown of arginase I. Since multiple alternative factors may combine to inhibit adaptive immunity, we propose that targeting macrophage differentiation may be a more effective strategy than targeting individual suppressive pathways.
authors.affiliation: a  Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, Oregon;
authors.forename: Marka R
authors.initials: MR
authors.lastname: Crittenden
authors.forename: Talicia
authors.initials: T
authors.lastname: Savage
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cottam
authors.forename: Jason
authors.initials: J
authors.lastname: Baird
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
authors.forename: Pippa
authors.initials: P
authors.lastname: Newell
authors.forename: Kristina
authors.initials: K
authors.lastname: Young
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Jackson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gough
mesh_terms: D056704:Adaptive Immunity / Q000528:radiation effects; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019583:Dose Fractionation, Radiation; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D055786:Gene Knockout Techniques; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism* / Q000528:radiation effects*; D018365:Neoplasm, Residual; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*
chemical_list: C544448:Arg1 protein, mouse; D001119:Arginase