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@ARTICLE{Goldschmid:275795,
      author       = {H. Goldschmid and K. Kluck and M. Ball and M. Kirchner and
                      M. Allgäuer and H. Winter and F. Herth and C.-P. Heußel
                      and S. S. Pullamsetti and R. Savai and T. T. K. Yong and P.
                      Schirmacher$^*$ and S. Peters and M. Thomas and P.
                      Christopoulos and J. Budczies$^*$ and A. Stenzinger$^*$ and
                      D. Kazdal},
      title        = {{S}patial profiling of the microenvironment reveals low
                      intratumoral heterogeneity and {STK}11-associated immune
                      evasion in therapy-naïve lung adenocarcinomas.},
      journal      = {Lung cancer},
      volume       = {180},
      issn         = {0169-5002},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2023-00883},
      pages        = {107212},
      year         = {2023},
      abstract     = {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.},
      keywords     = {Intertumoral heterogeneity (Other) / Lung adenocarcinoma
                      (Other) / STK11 (Other) / TME (Other) / Tumor
                      microenvironment (Other)},
      cin          = {HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)HD01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37141769},
      doi          = {10.1016/j.lungcan.2023.107212},
      url          = {https://inrepo02.dkfz.de/record/275795},
}