1. Academic Validation
  2. ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3

ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3

  • J Immunother Cancer. 2023 Dec 26;11(12):e007766. doi: 10.1136/jitc-2023-007766.
Yong-Qiang Ao # 1 2 Jian Gao # 1 2 Chun Jin # 3 Shuai Wang # 1 2 Li-Cheng Zhang 4 Jie Deng 5 Zong-Wei Chen 1 2 Hai-Kun Wang 6 Jia-Hao Jiang 7 2 Jian-Yong Ding 7 2
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China.
  • 2 Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China.
  • 3 Department of Thoracic Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
  • 4 School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 5 Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 6 CAS Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Beijing, China.
  • 7 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China ding.jianyong@zs-hospital.sh.cn jiang.jiahao@zs-hospital.sh.cn.
  • # Contributed equally.
Abstract

Background: Activating signal cointegrator 3 (ASCC3) has been identified as an oncogenic factor that impairs host immune defense. However, the underlying mechanisms of carcinogenesis and its impact on the antitumor immune response remain unclear. In this study, we aimed to investigate the molecular mechanisms of ASCC3 in the progression of non-small cell lung Cancer (NSCLC).

Methods: Single-cell Sequencing data from the Gene Expression Omnibus and gene expression profiles from The Cancer Genome Atlas database were analyzed. The expression, clinical relevance and biological functions of ASCC3 in NSCLC were explored. Then, RNA Sequencing, immunoprecipitation, mass spectrometry, immunofluorescence, and flow cytometry analyses were conducted to explore the underlying molecular mechanisms. In addition, in vivo experiments in mouse models were conducted to explore the probability of ASCC3 knockdown to improve the efficacy of anti-Programmed Death-1 (PD-1) therapy in NSCLC.

Results: ASCC3 was significantly upregulated in NSCLC and correlated with poor pathological characteristics and prognosis in patients with NSCLC. Overexpression of ASCC3 promoted malignant phenotypes of NSCLC cells and induced an immunosuppressive tumor microenvironment, which was characterized by a decrease in CD8+ T cells, natural killer cells and dendritic cells but an increase in regulatory T(Treg) cells. Mechanistically, ASCC3 stabilized signal transducer and activator of transcription (STAT)3 signaling by recruiting Cullin-associated and neddylation dissociated 1 (CAND1), which inhibited ubiquitin-mediated degradation of STAT3, thereby impairing the type I interferon response of tumor cells and promoting the immunosuppression and progression of NSCLC. Furthermore, high expression of ASCC3 impaired the efficacy of anti-PD-1 therapy, and an anti-PD-1 antibody combined with ASCC3 knockdown exerted promising synergistic efficacy in a preclinical mouse model.

Conclusion: ASCC3 could stabilize the STAT3 pathway via CAND1, reshaping the tumor microenvironment and inducing resistance to anti-PD-1 therapy, which promotes the progression of NSCLC. It is a reliable prognostic indicator and can be a target in combination therapy for NSCLC.

Keywords

Immunotherapy; Lung Neoplasms; Tumor Microenvironment.

Figures
Products