Addressing Immune Response Dysfunction in an Integrated Approach for Testing and Assessment for Non-Genotoxic Carcinogens in Humans: A Targeted Analysis.

Most known chemical carcinogens induce the direct activation of DNA damage, either directly or following metabolic activation. However, carcinogens do not always operate directly through genotoxic mechanisms but can do so via non-genotoxic carcinogenic (NGTxC) mechanisms. Immune dysfunction is one of these key events that NGTxCs have been shown to modify. The immune system is a first line of defence against transformed cells, with an innate immune response against cancer cells and mechanisms of immune evasion. Here, we review the key events of immune dysfunction. These include immunotoxicity, immune evasion, immune suppression and inflammatory-mediated immune responses, and the key players in the molecular disruption of immune anti-cancer molecular signalling pathways, particularly those mediated by cytokines and the Aryl hydrocarbon Receptor, in relation to the identification of NGTxC. The plasticity of cytokines towards functional flexibility in response to environmental stressors is also discussed from an evolutionary heritage perspective. This is combined with a critical assessment of the suitability for the regulatory application of currently available test method tools and is corroborated by the key biomarkers of, e.g., MAPK, mTOR, PD-L1, TIL and Tregs, CD8+, FoxP3+, WNT, IL-17, IL-11, IL-10, and TNFα, as identified from robust cancer biopsy studies. Finally, an understanding of how to address these endpoints for chemical hazard regulatory purposes, within an integrated approach to testing and assessment for NGTxC, is proposed.