BMI1 Inhibition Eliminates Residual Cancer Stem Cells after PD1 Blockade and Activates Antitumor Immunity to Prevent Metastasis and Relapse

• Published in: Cell stem cell 2020-08, Vol.27 (2), p.238-253.e6
• Main Authors: Jia, Lingfei, Zhang, Wuchang, Wang, Cun-Yu
• Format: Article
• Language: English
• Subjects: antitumor immune response; BMI1; cancer stem cells; CD8+ T cells; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Head and Neck Neoplasms; HNSCC; Humans; immunotherapy; invasive growth; metastasis; Neoplasm Recurrence, Local - prevention & control; Neoplastic Stem Cells; PD1 blockade; Polycomb Repressive Complex 1; squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2020.06.022

PD1 blockade-based combination therapy has been approved as a first-line treatment for head and neck squamous cell carcinoma (HNSCC). However, the response rate remains relatively low, and patients with HNSCC eventually relapse. Here, we show that the combination treatment of anti-PD1 and cisplatin enriched BMI1+ CSCs in HNSCC while inhibiting HNSCC growth. In contrast, the pharmacological and genetic inhibition of BMI1 eliminated BMI1+ CSCs and enabled PD1 blockade therapy, resulting in the inhibition of metastatic HNSCC and prevention of HNSCC relapses. BMI1 inhibition strongly induced tumor cell-intrinsic immune responses by recruiting and activating CD8+ T cells in addition to eliminating BMI1+ CSCs. Mechanistically, BMI1 inhibition induced CD8+ T cell-recruiting chemokines by stimulating IRF3-mediated transcription and erasing repressive H2A ubiquitination. Our results suggest that targeting BMI1 may enable immune checkpoint blockade to inhibit metastatic tumor growth and prevent tumor relapse by activating cell-intrinsic immunity, in addition to purging CSCs. [Display omitted] •BMI1+ CSCs enriched in HNSCC after cisplatin plus anti-PD1 treatment•BMI1 inhibitor plus anti-PD1 eliminates BMI1+ CSCs and inhibits tumor progression•BMI1 inhibition increased type 1 IFN chemokines and CD8+ T cell infiltration•BMI1 inhibitor plus anti-PD1 prevents BMI1+ CSCs-mediated tumor relapse Jia et al. show that the pharmacological or genetic inhibition of BMI1 helps not only to eliminate BMI1+ CSCs but also to augment PD1 blockade by activating tumor cell-intrinsic immunity, resulting in the inhibition of metastatic tumor growth and the prevention of tumor relapse.