Table 1.

Mechanism of primary and acquired resistance to checkpoint inhibitor^[99]

Primary resistance
Tumor cell	Low mutation burden/ Lack of neo-antigen Lower MHC-I expression Defects in β2M T-cell exclusion program Overexpression of VEGF Activation of PI3K-AKT and WNT/β-catenin pathways Mutations in the IFN-γ pathway. Epigenetic modulation of antigen processing and cytokine production
Tumor microenvironment	Severe Exhaustion of T-cells Increase in number and activity of MDSC in the tumor microenvironment Increase in Tumor associated macrophage Production of metabolic inhibitors like IDO-1 and adenosine in the tumor microenvironment Immunosuppressive cytokines like TGF-β, IL-10
Acquired resistance	Defects in β2M JAK1/2 mutation Presence of alternative checkpoints

MHC: major histocompatibility complex; VEGF: vascular endothelial growth factor; PI3K: phosphoinositide-3-Kinase; AKT: protein kinase B; IFN: interferon; MDSCs: Myeloid-derived suppressor cells; IDO: indoleamine-2,3 dioxygenases; TGF: tumor growth factor; IL: interleukin