Specific TP53 subtype as biomarker for immune checkpoint inhibitors in lung adenocarcinoma
Hao Sun1, Si-Yang Liu1, Jia-Ying Zhou1
1Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou 510080, China.
Background:
Although TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported.
Methods:
An integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway.
Findings:
The TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy.
Interpretation:
Our study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs.
Funding:
The study was supported by Key Lab System Project of Guangdong Science and Technology Department - Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU).
Insights
Not all TP53 mutations predict immune checkpoint inhibitor (ICI) response in lung adenocarcinoma (LUAD). Missense mutations show better response to anti-PD-1/1L therapy, while both types benefit from combination therapy.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- TP53 co-mutations predict immune checkpoint inhibitor (ICI) response in lung adenocarcinoma (LUAD).
- However, the distinct predictive roles of TP53 missense versus nonsense mutations for ICI efficacy remain underexplored.
- Understanding this heterogeneity is crucial for personalized LUAD treatment.
Purpose of the Study:
- To investigate the differential impact of TP53 missense and nonsense mutations on ICI treatment outcomes in LUAD patients.
- To explore the underlying mechanisms, including immune microenvironment and DNA damage repair pathways.
- To identify distinct biomarkers for predicting ICI response in LUAD.
Main Methods:
- Integrated analysis of genomic, transcriptomic, proteomic, and clinical data from LUAD patients.
- Gene Set Enrichment Analysis (GSEA) and Single-sample GSEA (GSVA) to assess gene signatures and DNA damage repair (DDR) pathways.
- Evaluation of PD-L1 expression, tumor mutational burden (TMB), neoantigen levels, and immune cell infiltration.
Main Results:
- TP53 missense mutations correlated with higher PD-L1 levels and enriched IFN-γ signatures, unlike nonsense mutations.
- Both TP53 missense and nonsense mutations were associated with increased TMB, neoantigen levels, and DNA damage repair deficiency.
- TP53 missense, but not nonsense, mutations predicted better clinical benefits with anti-PD-1/1L therapy; however, all TP53 subgroups responded to combination therapy.
Conclusions:
- TP53 mutation type significantly influences ICI efficacy and tumor microenvironment composition in LUAD.
- Missense mutations are associated with distinct immune profiles and better response to single anti-PD-1/1L therapy.
- TP53 mutation heterogeneity is critical for optimizing biomarker strategies in LUAD immunotherapy.
