The APOE–TREM2 Axis Mediates Senescent Neutrophils in Prostate Cancer

Enhanced numbers of immunosuppressive neutrophils promote tumor proliferation, immune suppression, and treatment resistance in many cancer types, including prostate cancer. Typically, in healthy subjects, neutrophils are characterized by a short half-life, but it currently remains undetermined whether immunosuppressive neutrophils that are critical to tumorigenesis persist within the tumor microenvironment (TME). Bancaro and colleagues sought to address this issue and showed that tumor-infiltrating immunosuppressive neutrophils express markers of cellular senescence and persist in the TME, where they are especially high in castration-resistant disease. These senescent neutrophils demonstrated enhanced immunosuppressive activity and protumorigenic function, and investigation into factors secreted by tumor cells that can regulate this phenotype revealed that prostate tumor cell secretion of apolipoprotein E (APOE) binds to TREM2 on neutrophils and activates downstream ERK signaling to induce senescence. In patients with prostate cancer, TREM2 expression correlated with a senescent neutrophil signature, disease progression, and poor prognosis, with APOE expression also correlating with poor disease-free and overall survival. Elimination of these senescent neutrophils in murine models of prostate cancer reduced tumor progression, supporting the protumorigenic role of these cells. Moreover, histone deacetylase (HDAC) inhibitors demonstrated the ability to eliminate these pathogenic cells through reduction of TREM2, and combination of the HDAC inhibitor romidepsin with the androgen receptor signaling inhibitor enzalutamide significantly reduced the number of immunosuppressive senescent neutrophils as well as tumor cell proliferation. Use of this combination along with the CXCR2 inhibitors, which are currently under clinical evaluation in prostate cancer, showed an even greater inhibition of immunosuppressive senescent neutrophils and prostate cancer progression. In conclusion, this work shows that neutrophils can persist in the prostate cancer TME by acquiring markers of senescence and suggests that targeting this cell population can improve outcomes in patients with this disease.

Bancaro N, Calì B, Troiani M, Elia AR, Arzola RA, Attanasio G, et al. Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer. Cancer Cell 2023;41:602–19.e11.

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