title: IDO is a nodal pathogenic driver of lung cancer and metastasis development.
abstract: Indoleamine 2,3-dioxygenase (IDO) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies, indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of the impact of IDO on tumorigenesis in physiologic models of primary or metastatic disease is lacking. Investigating the impact of Ido1 gene disruption in mouse models of oncogenic KRAS-induced lung carcinoma and breast carcinoma-derived pulmonary metastasis, we have found that IDO deficiency resulted in reduced lung tumor burden and improved survival in both models. Micro-computed tomographic (CT) imaging further revealed that the density of the underlying pulmonary blood vessels was significantly reduced in Ido1-nullizygous mice. During lung tumor and metastasis outgrowth, interleukin (IL)-6 induction was greatly attenuated in conjunction with the loss of IDO. Biologically, this resulted in a consequential impairment of protumorigenic myeloid-derived suppressor cells (MDSC), as restoration of IL-6 recovered both MDSC suppressor function and metastasis susceptibility in Ido1-nullizygous mice. Together, our findings define IDO as a prototypical integrative modifier that bridges inflammation, vascularization, and immune escape to license primary and metastatic tumor outgrowth.
  
  
  CONCLUSIONS
  This study provides preclinical, genetic proof-of-concept that the immunoregulatory enzyme IDO contributes to autochthonous carcinoma progression and to the creation of a metastatic niche. IDO deficiency in vivo negatively impacted both vascularization and IL-6–dependent, MDSC-driven immune escape, establishing IDO as an overarching factor directing the establishment of a protumorigenic environment.
authors: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA.
authors: Courtney
authors: C
authors: Smith
authors: Mee Young
authors: MY
authors: Chang
authors: Katherine H
authors: KH
authors: Parker
authors: Daniel W
authors: DW
authors: Beury
authors: James B
authors: JB
authors: DuHadaway
authors: Hollie E
authors: HE
authors: Flick
authors: Janette
authors: J
authors: Boulden
authors: Erika
authors: E
authors: Sutanto-Ward
authors: Alejandro Peralta
authors: AP
authors: Soler
authors: Lisa D
authors: LD
authors: Laury-Kleintop
authors: Laura
authors: L
authors: Mandik-Nayak
authors: Richard
authors: R
authors: Metz
authors: Suzanne
authors: S
authors: Ostrand-Rosenberg
authors: George C
authors: GC
authors: Prendergast
authors: Alexander J
authors: AJ
authors: Muller
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D011905:Genes, ras; D018922:HL-60 Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology; D015850:Interleukin-6 / Q000096:biosynthesis; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000201:enzymology; D016019:Survival Analysis; D020298:U937 Cells
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015850:Interleukin-6