Understanding how immune maturity shapes responses to cancer therapy

Abstract

Abstract Clinical translation of cancer therapies from mice to human remains a constant challenge. Cancer immunotherapy aims develop a sustained long-term adaptive immune response to tumors. This raises the question of whether the typical pathogen-free animal models reflect the human immunological context and cancer pathology. Recent research suggests that exposure of pathogen-free mice to pet shop mice leads to their immunological maturation. We hypothesize that such a model may be more reflective of a human adult context. Specific-pathogen-free (SPF) Balb/c mice were co-housed with pet shop mice for 40 days to generate the “dirty mouse” model. Dirty mice were challenged with Listeria m. infection to test immune maturity. In parallel, CT26LacZ, CT26WT, EMT6 and K7M2 tumor cell lines were used to measure tumor growth in dirty mice. In particular, CT26LacZ tumor model was treated with oncolytic virus to assess the impact of immune maturity over efficacy of therapy. Complementary comparative experiments were performed in SPF mice. Dirty mouse immune response to Listeria challenge was more robust than in clean mice. Immune phenotyping revealed a different distribution of immune populations. A matured immune system impacted the growth of tumors to varying extents, with some models experiencing complete tumor rejection. Finally, oncolytic virus in dirty mice implanted with CT26-LacZ showed an improved efficacy on survival and tumor burden. Immune response to infections and tumor models between SPF mice and dirty mice reveals the potential impact of a mature immune system on immune-therapeutic responses. Therefore, establishment of model that better recreates the state of immune maturity may result in higher chances of translational impact.