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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE286508 | GEO | 2026/02/03

REPOSITORIES: GEO

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Project description:This ordinary differential equation model simulating the mechanisms that govern cancer-immune dynamics and their role in tumor responses to immunotherapy is described by the publication: Creemers JHA, Lesterhuis WJ, Mehra N, et al. "A tipping point in cancer-immune dynamics leads to divergent immunotherapy responses and hampers biomarker discovery." Journal for ImmunoTherapy of Cancer 2021;9:e002032. doi:10.1136/jitc-2020-002032 Comment: Simulation parameters in supplementary table 1 mismatch with figure 1 in manuscript. Therefore, to clarify, the following parameter values were used: Reproduction of Fig. 1(C), xi = 0.0005 Reproduction of Fig. 1(D), xi = 0.00025 Abstract: Background: Predicting treatment response or survival of cancer patients remains challenging in immuno-oncology. Efforts to overcome these challenges focus, among others, on the discovery of new biomarkers. Despite advances in cellular and molecular approaches, only a limited number of candidate biomarkers eventually enter clinical practice. Methods: A computational modeling approach based on ordinary differential equations was used to simulate the fundamental mechanisms that dictate tumor-immune dynamics and to investigate its implications on responses to immune checkpoint inhibition (ICI) and patient survival. Using in silico biomarker discovery trials, we revealed fundamental principles that explain the diverging success rates of biomarker discovery programs. Results: Our model shows that a tipping point—a sharp state transition between immune control and immune evasion—induces a strongly non-linear relationship between patient survival and both immunological and tumor-related parameters. In patients close to the tipping point, ICI therapy may lead to long-lasting survival benefits, whereas patients far from the tipping point may fail to benefit from these potent treatments. Conclusion: These findings have two important implications for clinical oncology. First, the apparent conundrum that ICI induces substantial benefits in some patients yet completely fails in others could be, to a large extent, explained by the presence of a tipping point. Second, predictive biomarkers for immunotherapy should ideally combine both immunological and tumor-related markers, as a patient’s distance from the tipping point can typically not be reliably determined from solely one of these. The notion of a tipping point in cancer-immune dynamics helps to devise more accurate strategies to select appropriate treatments for patients with cancer.

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

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