Addressing Immune Response Dysfunction in an Integrated Approach for Testing and Assessment for Non-Genotoxic...

Area of Science:

• Toxicology
• Immunology
• Carcinogenesis

Background:

• Chemical carcinogens typically induce DNA damage, but non-genotoxic carcinogenic (NGTxC) mechanisms also exist.
• Immune dysfunction, including immunotoxicity and immune evasion, is a key event modulated by NGTxCs.
• The immune system is crucial for detecting and eliminating transformed cells.

Purpose of the Study:

• To review key events of immune dysfunction related to NGTxC.
• To identify molecular players disrupting anti-cancer immune signaling pathways.
• To assess regulatory applicability of current test methods and biomarkers for NGTxC.

Main Methods:

• Literature review focusing on immune dysfunction mechanisms and NGTxC.
• Analysis of molecular pathways involving cytokines and the Aryl hydrocarbon Receptor.
• Evaluation of biomarkers from cancer biopsy studies for regulatory use.

Main Results:

• Key immune dysfunction events include immunotoxicity, immune evasion, and suppression.
• Cytokines and the Aryl hydrocarbon Receptor are critical in NGTxC-mediated immune disruption.
• Biomarkers such as MAPK, PD-L1, TILs, Tregs, and cytokines (IL-17, TNFα) are identified.

Conclusions:

• Understanding NGTxC-induced immune dysfunction is vital for chemical hazard assessment.
• An integrated testing and assessment approach is proposed for NGTxC regulation.
• Biomarker validation is crucial for regulatory application in NGTxC identification.