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

Abdul Rafeh Naqash, Charalampos S Floudas, Etan Aber, Asaf Maoz, Amin H Nassar, Elio Adib, Khalil Choucair, Joanne Xiu, Yasmine Baca, Biagio Ricciuti, Joao V Alessi, Mark M Awad, Chul Kim, Julia Judd, Luis E Raez, Gilberto Lopes, Jorge J Nieva, Hossein Borghaei, Naoko Takebe, Patrick C MaBalazs Halmos, David J Kwiatkowski, Stephen V Liu, Hirva Mamdani

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)e2300371
JournalJCO Precision Oncology
Volume8
DOIs
StatePublished - Feb 2024

Keywords

  • Humans
  • Carcinoma, Non-Small-Cell Lung/drug therapy
  • Lung Neoplasms/drug therapy
  • Immune Checkpoint Inhibitors/pharmacology
  • Antineoplastic Agents, Immunological/therapeutic use
  • Progression-Free Survival
  • Tumor Microenvironment/genetics
  • Tumor Suppressor Protein p53/genetics
  • AMP-Activated Protein Kinase Kinases

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