Fig. 2

Pathways, genomic characteristics, and molecular mechanisms implicated in response to immune checkpoint therapy. Alterations in canonical cancer pathways such as the MAPK, PI3K, and WNT-β-catenin pathways are associated with increased resistance to ICB. Inactivation of the MAPK and PI3K pathways, through alterations such as PTEN loss, are associated with a reduction in TILs and decreased expression of pro-inflammatory cytokines in the TME. Conversely, activation of the WNT-β-catenin and IDO1 pathways results in suppression of T cells and NK cells in the TME. Genome-wide characteristics, including deficiencies in DNA repair machinery and increased tumor mutational/neoantigen burden, are also associated with resistance. Increased mutational burden has been shown to lead to an elevated neoantigen burden, which results in a highly immunogenic tumor. If the neoantigens are clonal, T cell response is capable of eradicating the entire tumor, rather than a subpopulation of tumor cells. Furthermore, decreased HLA variability, LoF alterations in the JAK-STAT pathway, and induction of TGFβ increase resistance to immune checkpoint therapy through alteration of the immune response directly. HLA human leukocyte antigen, ICB immune checkpoint blockade, IDO1 indoleamine 2,3-dioxygenase, JAK-STAT janus kinase/signal transducers and activators of transcription, LoF loss of function, MAPK mitogen-activated protein kinase, NK natural killer, PI3K phosphoinositide 3-kinase, PTEN phosphatase and tensin homolog, TGFβ transforming growth factor beta, TIL tumor infiltrating lymphocytes, TMB tumor mutational burden