Molecular model linking Th2 polarized M2 tumour‐associated macrophages with deaminase‐mediated cancer progression mutation signatures

A new and diverse range of somatic mutation signatures are observed in late‐stage cancers, but the underlying reasons are not fully understood. We advance a “combinatorial association model” for deaminase binding domain (DBD) diversification to explain the generation of previously observed cancer‐progression associated mutation signatures. We also propose that changes in the polarization of tumour‐associated macrophages (TAMs) are accompanied by the expression of deaminases with a new and diverse range of DBDs, and thus accounting for the generation of new somatic mutation signatures. The mechanism proposed is molecularly reminiscent of combinatorial association of heavy (H) and light (L) protein chains following V(D)J recombination of immunoglobulin molecules (and similarly for protein chains in heterodimers α/β and γ/δ of V(D)Js of T Cell Receptors) required for pathogen antigen recognition by B cells and T cells, respectively. We also discuss whether extracellular vesicles (EVs) emanating from tumour enhancing M2‐polarized macrophages represent a likely source of the de novo deaminase DBDs. We conclude that M2‐polarized macrophages extruding EVs loaded with deaminase proteins or deaminase‐specific transcription/translation regulatory factors and like information may directly trigger deaminase diversification within cancer cells, and thus account for the many new somatic mutation signatures that are indicative of cancer progression. This hypothesis now has a plausible evidentiary base, and it is worth direct testing in future investigations. A long‐term objective would be to identify molecular biomarkers predicting cancer progression (or metastatic disease) and to support the development of new drug targets before metastatic pathways are activated.