Figure 3.

Causal hypothesis of mutation burden and immune tolerance co-occurrence in human tumors. Pathogen concept (Part A). Both PD-1 ligand and APOBEC enzymes are induced after viral infection, via interferon gamma (IFNγ) secretion. The defensive anti-viral function of APOBEC3 results in off-target alterations within the host genome, which can be repaired by DNA repair processes, unless alteration of these functions. Carcinogen concept (Part B). Both PD-1 ligand and APOBEC enzymes are regulated by the same factors, like exogenous activators. PKC has been linked to APOBEC3 and PD-L1 overexpression in distinct studies.³⁵ PKC can be activated by exogenous substances such as phorbol, which acts as a co-carcinogen and T-lymphocyte activator.³⁴ Clonal selection concept (Part C). Co-occurrence of kataegis-mutation process and expression of immune checkpoints such as PD-L1/2 leads to the accumulation of mutations and the tumor progression. In the presence of high level of mutation burden, only tumors that overexpress PD-L1 (and hence evade the immune system) survive. Other mechanisms of immune escape, not studied herein, could also be surgical. Abbreviations. APOBEC = apolipoprotein B editing complex; MMR = mismatch repair.