Chronic inflammation is associated with many cancers but its role during carcinogenesis is not clear. Here we have used transgenic mice that inducibly express the constitutively active mutant human Ras oncogenic RasV12G in the epidermis and other keratin 5 or Involucrin expressing epithelia in the mouse in order to create a simplified system for testing interactions between specific oncogenes and the immune system. In this model, activation of Ras causes rapid epidermal hyperplasia and under long term induction tumor formation. Our results show that activation of Ras in the skin causes a rapid increase of circulating and skin infiltrating neutrophils, associated with increased expression of pro-inflammatory cytokines such as KC and IL-1β as well as an increase in the population of skin draining lymph node CD4, CD25, Foxp3+ T regulatory cells. To test the relevance of neutrophilia on Ras-induced hyperplasia and T regulatory cell accumulation we used the RB6-HC5 antibody to deplete neutrophils prior to and during induction of Ras expression. We found that systemic neutrophil depletion during Ras expression led to reduced hyperplasia, cytokine production, and regulatory T cell numbers suggesting that a Ras-mediated cancer-promoting environment results from synergism between Ras expression, neutrophil infiltration and reduced T cell tumor surveillance.
