Poster Presentation 28th Lorne Cancer Conference 2016

Hck activity drives pulmonary inflammation and lung tumour progression in mice (#225)

Robert JJ O'Donoghue 1 2 , Andrew G Jarnicki 3 , Jessica Jones 3 , Ashleigh Poh 1 4 , Andrew R Lilja 3 , Frederic Masson 1 2 , Steven Bozinovski 5 , Cameron Nowell 6 , Maree C Faux 7 , Gary P Anderson 3 , Matthias Ernst 1 2
  1. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
  2. School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
  3. Pharmacology and Medicine, University of Melbourne, Carlton, Victoria, Australia
  4. Inflammation Division, Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia
  5. School of Health Sciences, Health Innovations Research Institute, RMIT University, Bundoora, Victoria, Australia
  6. Monash Centre for Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
  7. Structural Biology Division, Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the world. Polymorphisms and mutations in haematopoietic cell kinase (HCK) have been observed in patients with COPD and lung cancer while aberrant activation of Hck promotes the development of COPD hallmarks in the lungs of mice. We investigated the cellular mechanisms and cytokines underpinning Hck-driven pulmonary inflammation and cancer in mice. We used genetic complementation and bone marrow chimerism to investigate the contribution of the immune system to inflammation mice that harbour a constitutive active Hck (HckUp/Up). Inflammation was assessed by measuring cellular and cytokine content of bronchoalveolar lavage fluid (BALF). Macrophage differentiation was assessed by flow cytometry of lung tissue from adult mice. Tumour development was assessed using an adenoviral Cre gene vector or tamoxifen-induced Scgb1a1-dependent Cre and KrasLSL-G12D/+ mice. Adult HckUp/Up mice develop pulmonary inflammation compared to Wt mice, which is linked to emphysema from 12 weeks of age. This phenotype was independent of the adaptive immune system since lymphocyte deficient (HckUp/Up;Rag1-/-) mice were similar to HckUp/Up mice. Phenotypic analysis of inflammatory cells in the lungs of mutant mice showed enhanced numbers and enrichment of CD11b+:Ly6g+:Csfr1+ myeloid-derived suppressor cells and CD11b+:F4/80+:Arg1+ alternatively activated macrophages. These cells were implicated in promoting disease after adoptive bone marrow transfers of Wt bone marrow alleviated disease and reduced MDSCs and AAMs in HckUp/Up host mice. Consistent with the tumour enhancing properties of these myeloid cells lung tumour burden was significantly increased in HckUp/Up;KrasLSL-G12D/+mice than in KrasLSL-G12D/+ and promoted adenoma formation in HckUp/Up;Scgb1a1CreErt2;KrasLSL-G12D/+  mice compared to the bronchiolar hyperplasia observed in control mice. In summary, Hck activity within pulmonary macrophages promotes MDSC accumulation and AAM differentiation to drive a COPD-like inflammatory pulmonary disease and lung tumour progression in mice.