fig4

Figure 4. Mechanisms of resistance to immuno-therapy. Cancer cells can express several immunosuppressive molecules that can be blocked using specific inhibitors in order to re-activate the anti-tumor immune response. Often, they are redundant so that the re-activation of one pathway may be compensated by hyperactivation of a different immunosuppressive route so that resistance to therapy is the result. Resistance to anti-PD1 blockade may be due to overproduction and release of VEGFA, as well as by overexpression of IDO1 with consequent increased levels of kynurein in the microenvironment. Specific components of the microbiota are also necessary for the successful blockade of PD-1 and CTL-A4 indicating that antibiotics may represent a resistance factor to ICIs. Finally, concurrent blockade of two or more immune checkpoints has been shown to improve the response and overcome the resistance to ICIs. Pembro: Pembrolizumab; Nivo: nivolumab; Rela: relatlimab; Ipi: ipilumab; IDO1: indoleamine 2, 3-dioxygenase 1.