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. 2019 May 21;20(10):2505. doi: 10.3390/ijms20102505

Figure 4.

Figure 4

Cross-talks between tumor and immune cells determining chemo-immune-resistance. Chemotherapy and immune cells, e.g., T-helper 17 (Th17) cells producing IL-17 and M2-polarized macrophages producing colony stimulating factor-1, activate the RAS/RAF/MEK/ERK pathway in tumor cells, leading to the up-regulation of the Bcl-2 proteins that promote chemoresistance by reducing apoptosis. Moreover, in response to chemotherapy, resistant tumors activate the RAS/RAF/MEK/ERK axis that: (i) up-regulates P-glycoprotein (Pgp), a drug efflux transporter and an inhibitor of the calreticulin (CRT)-triggered phagocytosis by dendritic cells (DCs), avoiding the establishment of a durable adaptive immune response mediated by CD8+ T-cells; (ii) promotes the secretion of kynurenine that expands the immune-suppressive T-regulatory (Treg) cells; (iii) up-regulates the immune-checkpoint ligand programmed death-1 ligand (PD-1L) that expands PD-1 rich/anergic CD4+ and CD8+ T-cells; (iv) down-regulates the surface protein NKG2D, preventing the cytotoxic activity of natural killer (NK) cells. Chemo-immune-resistance is sustained by either chemotherapy or immune cell-induced mechanisms, all converging on an increased ERK activation. Green arrows: decreased pathways (thin arrows) and events (thick arrows); red arrow: increased pathways (thin arrows) and events (thick arrows).