2. Academic Validation
  3. Inhibition of tumor intrinsic BANF1 activates antitumor immune responses via cGAS-STING and enhances the efficacy of PD-1 blockade

Inhibition of tumor intrinsic BANF1 activates antitumor immune responses via cGAS-STING and enhances the efficacy of PD-1 blockade

  • J Immunother Cancer. 2023 Aug;11(8):e007035. doi: 10.1136/jitc-2023-007035.
Minglei Wang # 1 2,  Yiheng Huang # 1,  Minxin Chen 1,  Weiyan Wang 3,  Fei Wu 1,  Tao Zhong 1,  Xiaozheng Chen 1,  Fei Wang 1,  Yang Li 1,  Jinming Yu 4 2 5,  Meng Wu 4,  Dawei Chen 4 2
Affiliations

Affiliations

  • 1 Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 2 Department of Oncology, Shandong University Cancer Center, Jinan, Shandong, China.
  • 3 School of Basic Medical Sciences, Shandong First Medical University, Jinan, Shandong, China.
  • 4 Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China [email protected] [email protected] [email protected].
  • 5 Research Unit of Radiation Oncology, Chinese Academy of Medical Sciences, Jinan, Shandong, China.
  • # Contributed equally.
PMID: 37620043 DOI: 10.1136/jitc-2023-007035
Abstract

Background: BANF1 is well known as a natural opponent of Cyclic GMP-AMP Synthase (cGAS) activity on genomic self-DNA. However, the roles of BANF1 in tumor immunity remain unclear. Here, we investigate the possible impact of BANF1 on antitumor immunity and response to immunotherapy.

Methods: The Cancer Genome Atlas public data were analyzed to evaluate the relevance of the expression of BANF1, patients' survival and immune cell infiltration. We monitored tumor growth and explored the antitumor efficacy of targeting tumor-intrinsic BANF1 in combination with anti-programmed cell death protein-1 (PD-1) in MC38 or B16F10 tumor models in both immunocompetent and immunodeficient mice. Flow cytometry, immunofluorescence and T cells depletion experiments were used to validate the role of BANF1 in tumor immune microenvironment reprogramming. RNA sequencing was then used to interrogate the mechanisms how BANF1 regulated antitumor immunity.

Results: We show that upregulated expression of BANF1 in tumor tissues is significantly associated with poor survival and is negatively correlated with immune cell infiltration. Deficiency of BANF1 in tumor cells markedly antagonizes tumor growth in immunocompetent but not immunocompromised mice, and enhances the response to immunotherapy in murine models of melanoma and colon Cancer. In the immunotherapy clinical cohort, patients with high BANF1 expression had a worse prognosis. Mechanistically, BANF1 knockout activates antitumor immune responses mediated by cGAS-synthase-stimulator of interferon genes (cGAS-STING) pathway, resulting in an immune-activating tumor microenvironment including increased CD8+ T cell infiltration and decreased myeloid-derived suppressor cell enrichment.

Conclusions: BANF1 is a key regulator of antitumor immunity mediated by cGAS-STING pathway. Therefore, our study provides a rational that targeting BANF1 is a potent strategy for enhancing immunotherapy for Cancer with BANF1 upregulation.

Keywords

CD8-Positive T-Lymphocytes; Immune Checkpoint Inhibitors; Lymphocytes, Tumor-Infiltrating; Melanoma; Tumor Microenvironment.

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