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Updated: Jul 2, 2026
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
APOBEC mutational signatures predict immune checkpoint inhibitor benefit in TMB-low metastatic NSCLC independent of
A Yaacov1, A Grinshpun1, R Gillis1
1Helmsley Cancer Center, Shaare Zedek Medical Center, Jerusalem, Israel; Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Background:
∼60%-70% of patients with metastatic non-small cell lung cancer (NSCLC) have relatively low tumor mutational burden (TMB), with limited biomarker-guided immunotherapy options beyond programmed death-ligand 1 (PD-L1) expression. APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) mutational signatures, defined by characteristic genomic footprints, are associated with higher TMB and a better response to immune checkpoint inhibitors (ICIs). However, whether APOBEC independently predicts ICI response in TMB-low tumors has not been established.
Materials And Methods:
We analyzed 857 ICI-treated and 1328 ICI-untreated TMB-low (<10 mut/Mb) patients with metastatic NSCLC from the MSK-CHORD cohort. APOBEC status was classified using MESiCA, a machine-learning algorithm for mutational signature detection from targeted gene panels. Predictive value was established through treatment interaction testing, multivariate adjustment, propensity score weighting, and landmark analyses. External validation included 82 TMB-low patients from published whole-exome sequencing studies.
Results:
APOBEC-positive patients (n = 52, 6.1%) had significantly improved overall survival [median 33.7 versus 17.4 months; hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.42-0.85, P = 0.004]. No such benefit was observed in ICI-untreated patients (HR 0.98, P = 0.85), with significant treatment interaction (P = 0.032), confirming a predictive rather than prognostic effect. APOBEC remained independently predictive after adjustment for PD-L1 status and age (adjusted HR 0.57, P = 0.002). The benefit was particularly pronounced in PD-L1-negative ICI-treated patients (HR 0.51, P = 0.002). The effect was robust across propensity score, landmark, and bootstrap analyses. External validation confirmed independent APOBEC benefit (adjusted HR 0.23, P = 0.020).
Conclusions:
APOBEC mutational signatures represent a robust predictive biomarker for ICI response in TMB-low metastatic NSCLC, identifying responders particularly among PD-L1-negative patients where biomarker guidance is most needed, detectable from targeted gene panels used in routine clinical practice.
Insights
APOBEC mutational signatures predict better response to immune checkpoint inhibitors in patients with low tumor mutational burden non-small cell lung cancer. This biomarker is particularly useful for PD-L1 negative patients, guiding immunotherapy decisions.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Metastatic non-small cell lung cancer (NSCLC) often presents with low tumor mutational burden (TMB), limiting immunotherapy options.
- Programmed death-ligand 1 (PD-L1) expression is a primary biomarker, but insufficient for many patients.
- APOBEC mutational signatures, linked to higher TMB, may offer alternative predictive value.
Purpose of the Study:
- To investigate if APOBEC mutational signatures independently predict immune checkpoint inhibitor (ICI) response in TMB-low metastatic NSCLC.
- To assess the predictive performance of APOBEC signatures, especially in PD-L1 negative patient subgroups.
Main Methods:
- Analysis of 857 ICI-treated and 1328 ICI-untreated TMB-low NSCLC patients from the MSK-CHORD cohort.
- APOBEC status determined by MESiCA, a machine-learning algorithm for targeted gene panels.
- Statistical validation including treatment interaction testing, multivariate adjustment, and external validation.
Main Results:
- APOBEC-positive patients showed significantly improved overall survival with ICI treatment (median 33.7 vs 17.4 months).
- No survival benefit was observed in ICI-untreated APOBEC-positive patients, confirming a predictive effect.
- APOBEC remained an independent predictor of ICI response, particularly beneficial in PD-L1-negative patients (HR 0.51).
Conclusions:
- APOBEC mutational signatures are a robust predictive biomarker for ICI response in TMB-low NSCLC.
- This signature identifies responders among PD-L1-negative patients, addressing a critical unmet need for biomarker guidance.
- APOBEC detection from targeted gene panels is feasible in routine clinical practice.
