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The immune response-related mutational signatures and driver genes in non-small-cell lung cancer

Hao Chen1,2, Wei Chong3, Changcai Teng4

  • 1Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.

Cancer Science
|June 22, 2019
PubMed

Insights

High tumor mutation burden and APOBEC signature predict response to immune checkpoint blockade in non-small-cell lung cancer. This combination improves immunotherapy efficacy and guides treatment decisions for NSCLC patients.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Immune checkpoint blockade (ICB) therapy offers significant clinical benefits for non-small-cell lung cancer (NSCLC).
  • Predictive biomarkers for ICB response in NSCLC remain largely unknown, hindering personalized treatment strategies.
  • Understanding the genomic landscape associated with ICB response is crucial for optimizing patient outcomes.

Purpose of the Study:

  • To identify reliable biomarkers predicting response to ICB therapy in NSCLC patients.
  • To investigate the association between somatic mutational profiles and ICB efficacy.
  • To explore the immunomodulatory effects of identified mutational signatures.

Main Methods:

  • Integration of somatic mutational profiles and clinicopathologic data from 113 NSCLC patients treated with ICB (CTLA-4/PD-1).
  • Analysis of tumor mutation burden (TMB), neoantigen burden, and specific mutational signatures (e.g., APOBEC).
  • Application of CIBERSORT algorithm for immune cell infiltration analysis and statistical tests (log-rank, odds ratio, hazard ratio, Fisher's exact test).

Main Results:

  • High TMB and neoantigen burden were significantly associated with improved ICB efficacy in NSCLC.
  • The apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature strongly correlated with ICB response (P = .001; OR, 0.18).
  • Combined high TMB and APOBEC signature demonstrated superior prediction of immunotherapy responders.
  • APOBEC activity correlated with increased CD4 memory activated T cells, CD8+ T cells, NK cells, and decreased regulatory T cells.
  • Specific gene mutations (IFNGR1, VTCN1 in responders; PTEN in non-responders) were identified.

Conclusions:

  • High TMB and the APOBEC mutational signature are key predictive biomarkers for ICB therapy in NSCLC.
  • The APOBEC signature influences the tumor immune microenvironment, enhancing T cell and NK cell activity.
  • These findings provide a basis for guiding immunotherapy selection and improving treatment strategies for NSCLC patients.
Keywords:
APOBEC signatureimmune checkpoint blockadeneoantigen burdennon-small-cell lung cancertumor mutation burden

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