Fig. 2.

Overview of the neoantigen production and presentation. Neoantigens can develop at the genomic level through SNVs, base INDELs and gene fusions, at the transcriptomic level through alternative splicing, polyadenylation (pA), RNA editing and allegedly non-coding regions, and at the proteomic level through dysregulated translation and PTMs. The integrated viral ORF is another source of neoantigens for cancers linked to viruses. The mutant peptides created by the proteasome-mediated breakdown of endogenous proteins are subsequently transported to the endoplasmic reticulum (ER) via transporters associated with antigen processing (TAP), where they may be loaded onto MHC-I. MHC-II dimers are assembled and bound to the invariant chain (Ii) in the ER. The Ii-MHC-II complex can be directly transported or sometimes indirectly internalized from the cell surface to the MHC-II compartment (MIIC), where the degradation of Ii by a series of endosomal proteases releases the MHC-II for binding a specific peptide derived from a mutant protein broken down in the endosomal pathway. These pMHC complexes will then traffic to the cell surface where they are recognized by T cells