Lydia Meder, Charlotte Isabelle Orschel, Cyrielle Bouchez, Rahil Gholamipoorfard, Claudia V. Orschel, David Stahl, Christoph Kreer, Mirjam Koker, Marieke Nill, Ilayda G. Kocak, Ka‐Won Noh, Xinlei Zhao, Leon Ullrich, Björn Häupl, Josefine Jakob, Marie‐Lisa Eich, Alexandra Florin, Holger Grüll, Juergen Wolf, Filippo Beleggia, Reinhard Büttner, Thomas Oellerich, Florian Klein, Johannes Brägelmann, Hans Christian Reinhardt, Nima Abedpour, Roland T. Ullrich
Small cell lung cancer (SCLC) is characterized by its highly aggressive phenotype and dismal outcome. Despite the benefit of adding immune checkpoint blockade to standard chemotherapy, tumors acquire the ability to evade immunosurveillance and develop resistance. To investigate these underlying mechanisms, we perform high-dimensional profiling of human and murine SCLC specimens. In matched primary and metastatic human samples, we observe MHC-I loss in metastases, highlighting its role in immune evasion. Correspondingly, silencing MHC-I in SCLC cells drastically reduces immune infiltration and promotes metastasis in mice. Using mass spectrometry and phospho-tyrosine kinase analyses, we identify ERBB2 signaling as a suppressor of MHC-I and driver of immune-modulatory transcripts. Mechanistically, genetic and pharmacologic blockade of ERBB2 induces MHC-I in a STING-dependent manner and prevents immune evasion in autochthonous murine SCLC. Strikingly, combining ERBB2 inhibition with anti-PD-1 elicits profound synergistic responses in preclinical models, suggesting this combination for future clinical trials in SCLC patients.