Influence of TP53 Comutation on the Tumor Immune Microenvironment and Clinical Outcomes With Immune Checkpoint Inhibitors in STK11-Mutant Non-Small-Cell Lung Cancer

PURPOSE Non–small-cell lung cancer (NSCLC) with STK11 ^mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of STK11 ^mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring TP53 comutations could have favorable outcomes to ICIs. PATIENTS AND NSCLC tumors (N 5 16,896) were analyzed by next-generation sequencing METHODS (DNA-Seq/592 genes). A subset (n 5 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11 ^mut 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 5 34) and the study by Rizvi et al (n 5 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n 5 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for STK11 ^mutTP53 ^mut versus STK11 ^mutTP53 ^wt NSCLC. RESULTS Overall, 12.6% of NSCLC tumors had a STK11 ^mut 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 STK11 ^mut (n 5 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in TP53 ^mut NSCLC (P < .01). Compared with STK11 ^mutTP53 ^wt, tumors with STK11 ^mutTP53 ^mut had higher CD81T 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 STK11 ^mutTP53 ^mut. In the DFCI cohort, compared with the STK11 ^mut TP53 ^wt cohort, the STK11 ^mutTP53 ^mut tumors had higher objective response rates (42.9% v 16.7%; P 5 .04) and also had longer TTF (14.5 v 4.5 months, P adj 5 .054) with ICI. CONCLUSION STK11 ^mut 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.