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

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, whi...

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Main Authors: Goldschmid, Hannah (Author) , Kluck, Klaus (Author) , Ball, Markus (Author) , Kirchner, Martina (Author) , Allgäuer, Michael (Author) , Winter, Hauke (Author) , Herth, Felix (Author) , Heußel, Claus Peter (Author) , Pullamsetti, Soni Savai (Author) , Savai, Rajkumar (Author) , Yong, Timothy Tay Kwang (Author) , Schirmacher, Peter (Author) , Peters, Solange (Author) , Thomas, Michael (Author) , Christopoulos, Petros (Author) , Budczies, Jan (Author) , Stenzinger, Albrecht (Author) , Kazdal, Daniel (Author)
Format: Article (Journal)
Language:English
Published: June 2023
In: Lung cancer
Year: 2023, Volume: 180, Pages: 1-9
ISSN:1872-8332
DOI:10.1016/j.lungcan.2023.107212
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.lungcan.2023.107212
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S016950022300750X
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Author Notes:Hannah Goldschmid, Klaus Kluck, Markus Ball, Martina Kirchner, Michael Allgäuer, Hauke Winter, Felix Herth, Claus-Peter Heußel, Soni Savai Pullamsetti, Rajkumar Savai, Timothy Tay Kwang Yong, Peter Schirmacher, Solange Peters, Michael Thomas, Petros Christopoulos, Jan Budczies, Albrecht Stenzinger, Daniel Kazdal
Description
Summary: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.
Item Description:Online verfügbar: 23. April 2023, Artikelversion: 2. Mai 2023
Gesehen am 15.08.2023
Physical Description:Online Resource
ISSN:1872-8332
DOI:10.1016/j.lungcan.2023.107212

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