Fig. 3

Immunosuppressive milieu in the tumor immune microenvironment (TIM). On the tumor side, tumor cells could evade the attack from T effector cells (Teff) by concealing the MHC complex, inhibit the function of Teff by up-regulation of PD-L1, and induce the apoptosis of Teff by up-regulation FasL. Some metabolic pathways related to immune suppression also increased in tumor cells, such as IDO. The up-regulation of CD47 plays as a “Don’t eat me” signal to evade the phagocytosis of macrophages via CD47/SIRPα. For T cells in the TIM, suppressive immune checkpoint molecules were upregulated, including PD-1, CTLA-4, TIM3, LAG3, 2B4. For NK cells in the TIM, upregulated immunosuppressive molecules include KIR, NKG2A, TIM3. For Treg cells, chemokine receptors upregulation contributes to the infiltration of Treg and the role of immunomodulation. Many other immunomodulatory molecules also contributes to the suppressive TIM. For example, IL-10,TGF-β, adenosine could play as anti-inflammatory cytokines to suppress the function of T cells and NK cells in the TIM; Colony-stimulating factor-1 (CSF-1) could recruit more M2 macrophages (Mϕ II) and myeloid-derived suppressor cells (MDSC)