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

Goldschmid, Hannah; Kluck, Klaus; Ball, Markus; Kirchner, Martina; Allgaeuer, Michael; Winter, Hauke; Herth, Felix; Heussel, Claus-Peter; Pullamsetti, Soni Savai; Savai, Rajkumar; Yong, Timothy Tay Kwang; Schirmacher, Peter; Peters, Solange; Thomas, Michael; Christopoulos, Petros; Budczies, Jan; Stenzinger, Albrecht; Kazdal, Daniel

doi:10.1016/j.lungcan.2023.107212

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

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Pullamsetti, Soni Savai
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Savai, Rajkumar
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Goldschmid, H., Kluck, K., Ball, M., Kirchner, M., Allgaeuer, M., Winter, H., et al. (2023). Spatial profiling of the microenvironment reveals low intratumoral heterogeneity and STK11-associated immune evasion in therapy-naive lung adenocarcinomas. LUNG CANCER, 180: 107212. doi:10.1016/j.lungcan.2023.107212.

Cite as: https://hdl.handle.net/21.11116/0000-000D-68DE-5

Abstract

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