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

Abstract

Non-small-cell lung cancer (NSCLC) with <i>STK11</i>^mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of <i>STK11</i>^mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring <i>TP53</i> comutations could have favorable outcomes to ICIs. 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 <i>STK11</i>^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 = 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 <i>STK11</i>^mut<i>TP53</i>^mut versus <i>STK11</i>^mut<i>TP53</i>^wt NSCLC. Overall, 12.6% of NSCLC tumors had a <i>STK11</i>^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 <i>STK11</i>^<i>mut</i> (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in <i>TP53</i>^mut NSCLC (<i>P</i> < .01). Compared with <i>STK11</i>^mut<i>TP53</i>^wt, tumors with <i>STK11</i>^mut<i>TP53</i>^mut had higher CD8+T cells and natural killer cells (<i>P</i> < .01), higher TMB (<i>P</i> < .001) and neoantigen load (<i>P</i> < .001), and increased expression of <i>MYC</i> and <i>HIF-1A</i> (<i>P</i> < .01), along with higher expression (<i>P</i> < .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 <i>STK11</i>^mut<i>TP53</i>^mut. In the DFCI cohort, compared with the <i>STK11</i>^mut <i>TP53</i>^wt cohort, the <i>STK11</i>^mut<i>TP53</i>^mut tumors had higher objective response rates (42.9% <i>v</i> 16.7%; <i>P</i> = .04) and also had longer TTF (14.5 <i>v</i> 4.5 months, <i>P</i> adj = .054) with ICI. <i>STK11</i>^mut NSCLC with <i>TP53</i> 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.