Abstract LB049: Spatial immune determinants of ICB response in STK11-mutated non-small cell lung cancer

Abstract

Response to immune checkpoint blockade (ICB) in non-small cell lung cancers (NSCLC) is associated with recurring mutations in tumor suppressor genes STK11 and TP53. Whereas STK11-mutated patients are mostly insensitive, TP53-mutated patients commonly respond to ICB. Previous studies have linked mutational status in these genes to differences in cell type composition of the tumor microenvironment (TME). However, it remains unclear if differences in cell type compositions as well as cell-cell interactions in turn could account for the observed differences in treatment response and overall survival in NSCLC. Here, we perform spatial profiling of immune and stromal phenotypes in the TME of 119 NSCLC patients using imaging mass cytometry (IMC) on tissue microarrays (TMA). Matching data from MSK IMPACT (clinical sequencing) was used to establish mutation profiles and therapeutic response was included in the analysis. We find that STK11-mutated NSCLC is characterized by decreased CD4 T cell and increased neutrophil abundance, while TP53-mutated NSCLC is associated with increased CD8 T cell and decreased endothelial cell abundance. Accordingly, we stratified the patient population into TME classes by cell type composition. We found that while mutational status does not inform overall survival in our cohort, stratification by cell type abundance strongly associates with patient outcome (p-value: 0.000146, logRank test). Patients with neutrophil-rich TMEs show worse overall survival (25% 5-year survival), while patients with increased endothelial cell and macrophage abundance have a tendency to live longer (80% and 75% 5-year survival respectively). Furthermore, we interrogate pairwise proximity of immune cell types and states to construct cellular networks in NSCLC. Together, our findings suggest that TME cell type composition and cellular networks are potential molecular determinants for ICB therapeutic response in NSCLC patients. Citation Format: Florian Uhlitz, Douglas Linn, Elsa Beyer Krall, Jacklynn Egger, Hira Rizvi, Jason Chang, Benjamin Nicholson, Rami Vanguri, Andrew Chow, Matthew Hellmann, Sohrab Shah. Spatial immune determinants of ICB response in STK11-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB049.