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

Figure 2.

Figure 2

Mechanisms of ERK-induced immune-resistance or immune-escape. In response to chemokines and growth factors (GFs), specific tyrosine kinase receptors (TKR) activate the RAS/RAF/MEK/ERK axis and the down-stream transcription factors (TF) in tumor cells. As a result, cancer cells produce immune-suppressive cytokines [e.g., interleukin (IL)-10 and transforming growth factor-β (TGF-β)] and metabolites (e.g., kynurenine) that reduce the proliferation of effector CD4+ and CD8+T-lymphocytes and expand tumor-promoting/immune-suppressive cells, such as M2-polarized macrophages, myeloid derived suppressor cells (MDSC), and T-regulatory (Treg) cells. The RAS/RAF/MEK/ERK axis also up-regulates the immune-checkpoint ligand programmed death-1 ligand (PD-1L), which expands PD-1 rich/anergic CD4+ and CD8+ T-cells and fuels ERK activity with a positive feedback mechanism. Exploiting these multiple strategies, ERK activation in tumor cells contributes to create a tumor-promoting/immune-suppressive environment.