Spatial profiling of the microenvironment reveals low intratumoral heterogeneity and STK11-associated immune evasion in therapy-naïve lung adenocarcinomas

Lung Cancer. 2023 Jun:180:107212. doi: 10.1016/j.lungcan.2023.107212. Epub 2023 Apr 23.

Abstract

Objective: Intratumoral heterogeneity was found to be a significant factor causing resistance to lung cancer therapies, including immune checkpoint blockade. Lesser is known about spatial heterogeneity of the tumor microenvironment (TME) and its association with genetic properties of the tumor, which is of particular interest in the therapy-naïve setting.

Materials and methods: We performed multi-region sampling (2-4 samples per tumor; total of 55 samples) from a cohort of 19 untreated stage IA-IIIB lung adenocarcinomas (n = 11 KRAS mutant, n = 1 ERBB2 mutant, n = 7 KRAS wildtype). For each sample the expression of 770 immunooncology-related genes was analyzed using the nCounter platform, while the mutational status was determined by hybrid capture-based next-generation sequencing (NGS) using a large panel covering more than 500 genes.

Results: Global unsupervised analyses revealed clustering of the samples into two groups corresponding to a 'hot' or 'cold' immunologic tumor contexture based on the abundance of immune cell infiltrates. All analyzed specific immune cell signatures (ICsig) showed a significantly higher intertumoral than intratumoral heterogeneity (p < 0.02), as most of the analyzed cases (14/19) showed a very homogenous spatial immune cell profile. PD-L1 exhibited a significantly higher intertumoral than intratumoral heterogeneity (p = 1.03e-13). We found a specific association with 'cold' TME for STK11 (11/14, p < 0.07), but not KRAS, TP53, LRP1B, MTOR, U2AF1 co-mutations, and validated this finding using The Cancer Genome Atlas (TCGA) data.

Conclusion: Early-stage lung adenocarcinomas show considerable intertumoral, but limited intratumoral heterogeneity, which is clinically highly relevant as assessment before neoadjuvant treatment is based on small biopsies. STK11 mutations are specifically associated with a 'cold' TME, which could affect the efficacy of perioperative immunotherapy.

Keywords: Intertumoral heterogeneity; Lung adenocarcinoma; STK11; TME; Tumor microenvironment.

MeSH terms

  • AMP-Activated Protein Kinase Kinases* / genetics
  • Adenocarcinoma of Lung* / genetics
  • Adenocarcinoma of Lung* / immunology
  • Adenocarcinoma of Lung* / therapy
  • Humans
  • Immune Evasion* / genetics
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / therapy
  • Mutation
  • Neoplasm Staging
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology

Substances

  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases