Tumor-intrinsic ETV5 Expression Promotes MDSCs-mediated Immune Evasion and Immune Checkpoint Inhibitor Resistance

Immunotherapy remains ineffective for a wide variety of solid tumors due to the existence of tumor immune evasion. Patients with tumors expressing high levels of ETV5 respond poorly to immunotherapy, but the understanding of its impact on immune evasion is limited. Here, we reveal that tumor-intrinsic ETV5 drives immune evasion and immune checkpoint inhibitor (ICI) resistance by enhancing the expansion and recruitment of MDSCs. Knockdown of ETV5 in tumor cells reduces the generation of MDSCs from myeloid progenitors and their accumulation in the tumor microenvironment, leading to enhanced anti-tumor response presented by increased T cell infiltration, proliferation and reduced exhaustion. Mechanistically, ETV5 binds to JAK2 protein, facilitates its dimerization and elevates its phosphorylation status. Consequently, this promotes the phosphorylation of STAT3, which activates the transcription of CCL2, augmenting the recruitment of MDSCs. Finally, ETV5 deficiency reduces MDSCs and enriches anticancer T lymphocytes, thereby improving ICI efficacy in mice. Our findings shed light on the crucial role of tumor-intrinsic ETV5 in facilitating immune evasion and its fundamental mechanism. Furthermore, they offer a novel immunotherapy strategy targeting ETV5 for the treatment of solid tumors. Overall design: RNA-seq of wildtype 4T1 cells lines and their knockdown ETV5(shRNA)