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Updated: Nov 22, 2025
Author Spotlight: Advancing the Detection of Low-Frequency Mutations in Cancer Tissues
Published on: August 23, 2024
Alpha Thalassemia/Intellectual Disability X-Linked Deficiency Sensitizes Non-Small Cell Lung Cancer to Immune
Tao Hou1, Shun Jiang1, Yapeng Wang1
1Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China.
Background:
The immune checkpoint inhibitors (ICIs) have achieved great success in the treatment of non-small cell lung cancer (NSCLC) patients. However, the response rate is low. The molecular mechanism involved in the effectiveness of ICIs remains to be elucidated.
Methods:
ATRX mutation incidence among human cancers was analyzed from TCGA database. Atrx-deficient Lewis lung cancer cell line (LLC-sgAtrx) was established via AAV-CRISPR. Subcutaneous and metastasis models were established by subcutaneous and intravenous injection of LLC-sgAtrx and LLC-sgNTC cells into female C57BL/6 mice. The mice were treated with anti-PD1, anti-CLTA4 or Rat IgG2a. Tumor volume was determined by Vernier calipers and the IVIS imaging system. The proportions of CD3+ T cells, CD45+ immune cells, and the expression of pMHC I and PDL1 were determined by flow cytometry. The T cell cytotoxicity was determined by co-culture experiment.
Results:
TCGA data showed that Atrx is a tumor suppressor mutated at high frequency among various human cancers. The tumor volume of mice bearing LLC-sgAtrx was significantly shrinked and the median survival of mice was significantly longer after anti-PD1 and anti-CTLA4 treatment. Flowcytometry results showed that Atrx deficiency increase the penetration of CD3+ T cell into the tumor microenvironment and enhanced antigen presentation after IFNγ stimulation. Additionally, the tumor cells with Atrx deficiency were more easily to be damaged by T cells under IFNγ stimulation.
Conclusion:
The present study demonstrated that Atrx deficiency sensitize lung cancer cells to ICIs by multiple mechanisms. And ATRX may serve as a promising biomarker for ICIs which helps patient stratification and decision making.
Insights
ATRX deficiency enhances the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) by improving T cell infiltration and tumor cell sensitivity. ATRX may serve as a predictive biomarker for ICI therapy in NSCLC patients.
Area of Science:
- Oncology
- Immunology
- Cancer Genetics
Background:
- Immune checkpoint inhibitors (ICIs) show promise for non-small cell lung cancer (NSCLC) treatment.
- However, the low response rate necessitates understanding the underlying molecular mechanisms.
- The role of ATRX in ICI efficacy remains largely unknown.
Purpose of the Study:
- To investigate the role of ATRX deficiency in modulating the tumor immune microenvironment and response to ICIs in NSCLC.
- To explore ATRX as a potential predictive biomarker for ICI therapy.
Main Methods:
- Analysis of ATRX mutation frequency in human cancers using TCGA database.
- Establishment of Atrx-deficient Lewis lung cancer cell lines (LLC-sgAtrx) using CRISPR technology.
- In vivo studies involving subcutaneous and metastasis models in mice treated with anti-PD1 and anti-CTLA4 antibodies.
- Assessment of immune cell infiltration, antigen presentation, and T cell cytotoxicity via flow cytometry and co-culture experiments.
Main Results:
- TCGA data revealed ATRX as a frequently mutated tumor suppressor across various cancers.
- Mice bearing LLC-sgAtrx tumors exhibited significantly reduced tumor volume and prolonged survival following ICI treatment.
- ATRX deficiency increased CD3+ T cell infiltration into the tumor microenvironment and enhanced antigen presentation.
- Tumor cells with ATRX deficiency demonstrated increased susceptibility to T cell-mediated killing upon IFNγ stimulation.
Conclusions:
- ATRX deficiency sensitizes lung cancer cells to ICIs through multiple mechanisms, including enhanced T cell infiltration and cytotoxicity.
- ATRX emerges as a potential predictive biomarker for stratifying NSCLC patients and guiding ICI treatment decisions.
