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Influence of TP53 Comutation on the Tumor Immune Microenvironment and Clinical Outcomes With Immune Checkpoint
Abdul Rafeh Naqash1, Charalampos S Floudas2, Etan Aber2
1Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Purpose:
Non-small-cell lung cancer (NSCLC) with STK11mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of STK11mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring TP53 comutations could have favorable outcomes to ICIs.
Patients And Methods:
NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11mut NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for STK11mutTP53mut versus STK11mutTP53wt NSCLC.
Results:
Overall, 12.6% of NSCLC tumors had a STK11mut with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of STK11mut (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in TP53mut NSCLC (P < .01). Compared with STK11mutTP53wt, tumors with STK11mutTP53mut had higher CD8+T cells and natural killer cells (P < .01), higher TMB (P < .001) and neoantigen load (P < .001), and increased expression of MYC and HIF-1A (P < .01), along with higher expression (P < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with STK11mutTP53mut. In the DFCI cohort, compared with the STK11mut TP53wt cohort, the STK11mutTP53mut tumors had higher objective response rates (42.9% v 16.7%; P = .04) and also had longer TTF (14.5 v 4.5 months, P adj = .054) with ICI.
Conclusion:
STK11mut NSCLC with TP53 comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches.
Insights
Non-small-cell lung cancer (NSCLC) with STK11 mutations typically responds poorly to immune checkpoint inhibitors (ICIs). However, STK11-mutated NSCLC also harboring TP53 mutations shows an inflamed tumor immune microenvironment, suggesting potential benefit from ICIs.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Non-small-cell lung cancer (NSCLC) with STK11 mutations (STK11mut) generally exhibits poor outcomes with immune checkpoint inhibitors (ICIs).
- Identifying subgroups of STK11mut NSCLC that may benefit from ICIs is crucial for improving patient treatment strategies.
Approach:
- A multiomics approach analyzed 16,896 NSCLC tumors using next-generation sequencing and gene expression profiling.
- Tumor immune microenvironment (TIME) features, neoantigen load, and metabolic profiles were assessed in STK11mut NSCLC, particularly focusing on the impact of TP53 comutations.
- Immune checkpoint inhibitor (ICI) response data from multiple cohorts were used to model progression-free survival (PFS), time to treatment failure (TTF), and objective response rates.
Key Points:
- STK11mut NSCLC tumors co-occurring with TP53 mutations (STK11mutTP53mut) displayed a significantly inflamed TIME, characterized by increased CD8+ T cells, natural killer cells, higher tumor mutational burden (TMB), and elevated neoantigen load compared to STK11mutTP53 wild-type (wt) tumors.
- STK11mutTP53mut NSCLC exhibited metabolic reprogramming, with increased expression of glycolysis and glutamine metabolism genes, alongside elevated MYC and HIF-1A.
- Meta-analysis indicated a trend towards improved PFS with ICIs in STK11mutTP53mut NSCLC, and the DFCI cohort showed significantly higher objective response rates and longer TTF in this subgroup.
Conclusions:
- STK11mut NSCLC with TP53 comutation represents a distinct molecular and immunological subtype.
- This subgroup is characterized by an immunologically active TIME and metabolic alterations.
- These findings suggest that STK11mutTP53mut NSCLC patients may benefit from ICIs and support the exploration of novel ICI-based combination therapies for patient selection.
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