p21-Positive Senescent Stromal Cells Promote Prostate Cancer Immune Suppression and Progression That Can Be Reversed by Senolytic Therapy.

Cellular senescence is a well-established tumor-suppressive cell-cycle arrest program. However, chronic inflammation through the senescence-associated secretory phenotype (SASP) can alternatively drive immune suppression and cancer progression. Using prostate cancer patient samples and murine models, we find p16+ and p21+ senescent cells accumulate throughout malignant progression and associate with immune suppression. Single-cell sequencing revealed that p16 and p21 mark distinct epithelial and stromal senescent populations, with p21+ nontumor cells expressing the highest SASP. p21+ stromal cell removal blocked the SASP to reverse immune suppression and slow tumor growth. Senolytic BCL-xL inhibitor treatment could clear p21+ stromal senescent cells, reactivating antitumor CD8+ T-cell immunity and inhibiting prostate tumor progression in mice. Suppression of BCL-xL or p21 also potentiated anti-PD-1 immune checkpoint blockade (ICB) in preclinical prostate cancer models. Our findings demonstrate that targeting p21+ senescent stromal populations can yield therapeutic benefits in advanced prostate cancer through activating antitumor immunity and enhancing immunotherapy outcomes. SIGNIFICANCE: Senescent cells accumulate in the tumor and stroma throughout prostate cancer progression and are associated with immune suppression in patients and mice. Senolytic strategies to clear p21+ senescent stromal cells can prevent prostate cancer progression and reactive cytotoxic T-cell immunity to potentiate anti-PD-1 ICB in advanced disease.