TY  - JOUR
AU  - Goldschmid, Hannah
AU  - Kluck, Klaus
AU  - Ball, Markus
AU  - Kirchner, Martina
AU  - Allgäuer, Michael
AU  - Winter, Hauke
AU  - Herth, Felix
AU  - Heußel, Claus-Peter
AU  - Pullamsetti, Soni Savai
AU  - Savai, Rajkumar
AU  - Yong, Timothy Tay Kwang
AU  - Schirmacher, Peter
AU  - Peters, Solange
AU  - Thomas, Michael
AU  - Christopoulos, Petros
AU  - Budczies, Jan
AU  - Stenzinger, Albrecht
AU  - Kazdal, Daniel
TI  - Spatial profiling of the microenvironment reveals low intratumoral heterogeneity and STK11-associated immune evasion in therapy-naïve lung adenocarcinomas.
JO  - Lung cancer
VL  - 180
SN  - 0169-5002
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - DKFZ-2023-00883
SP  - 107212
PY  - 2023
AB  - 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.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.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.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.
KW  - Intertumoral heterogeneity (Other)
KW  - Lung adenocarcinoma (Other)
KW  - STK11 (Other)
KW  - TME (Other)
KW  - Tumor microenvironment (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37141769
DO  - DOI:10.1016/j.lungcan.2023.107212
UR  - https://inrepo02.dkfz.de/record/275795
ER  -