Fig. 6
Impact of oncogenic signaling on tumor immune response. a Loss of PTEN protein function and improper PI3K activation inhibit efficient LC3 lipidation, which further promote resistance to T-cell-mediated killing by inhibiting autophagy. PTEN loss could also induce expression of immunosuppressive cytokines, including CCL12 and VEGF. b CDK4/6 inhibition enhances T-cell activation through the derepression of NFAT family proteins and their target genes, which encodes critical regulators of T-cell function. CDK4/6 inhibition could also induce Rb-mediated G1-arrest and promote the phenotypic and functional acquisition of immunologic T-cell memory. Besides, the PD-L1 protein stability is regulated by the CDK4-SPOP-FZR1 signaling pathway. Physiologically, PD-L1 protein stability is negatively regulated through phosphorylating its upstream physiological E3 ligase SPOP. This phosphorylation promotes SPOP binding to 14-3-3Îł, which subsequently disrupts FZR1-mediated destruction of SPOP. The inhibition of CDK4/6 inhibits the phosphorylation of SPOP, thus promoting its degradation by FZR1, thus increasing PD-L1 protein levels. c Tumor-derived VEGF limits NF-ÎşB activation in immature DCs, which in turn leads to defective functional maturation of DCs and insufficient induction of tumor immunity. VEGF could also impact the endothelial cells expression of immunological molecules. It decreases the expression of VCAM-1, which is important for the antitumor T cells adhesion and infiltration into tumors. Besides, VEGF also increases the expression of FAS ligand on endothelial cells, triggering apoptosis of T cells. VEGF also promotes the expansion of immune suppressive MDSCs, which further promotes the recruitment of Tregs. d EZH2 inhibition increases the production of CXCL9 and CXCL10, which are attractant cytokines promoting trafficking of T cells to tumor. Besides, EZH2 inhibition could selectively target intratumeral Tregs and reduce its immunosuppressive capacity. e In tumor cells, the ablation of LSD1 in cancer cells increases repetitive element expression, including ERVs, and decreases expression of RISC components. This leads to dsRNA stress and activation of type 1 interferon, which stimulates antitumor T-cell infiltration. In addition, inhibiting LSD1 in CD8+ T cells unleashes the transcription program mediated by TCF1, which is critical for the maintenance of the progenitor subset of intratumoral CD8+ T cells for persistent tumor control. dsRNA double-stranded RNA, ERVs endogenous retroviral elements, MDSCs myeloid-derived suppressor cells, RISC RNA-induced silencing complex, TCF1 T-cell factor 1, VCAM-1 vascular cell adhesion molecule-1
