title: Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma.
abstract: Remarkable efficacy of immune checkpoint inhibition has been reported for several types of solid tumors and early studies in gastric adenocarcinoma are promising. A detailed knowledge about the natural biology of immune checkpoints in gastric adenocarcinoma is essential for clinical and translational evaluation of these drugs. This study is a comprehensive analysis of cytotoxic T lymphocyte associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) expression in gastric adenocarcinoma. PD-L1 and CTLA-4 were stained on tumor sections of 127 Caucasian patients with gastric adenocarcinoma by immunohistochemistry (IHC) and somatic mutation profiling was performed using targeted next-generation sequencing. Expression of PD-L1 and CTLA-4 on lymphocytes in tumor sections, tumor-draining lymph nodes (TDLN) and peripheral blood were studied by flow-cytometry and immune-fluorescence microscopy in an additional cohort. PD-L1 and CTLA-4 were expressed in 44.9% (57/127) and 86.6% (110/127) of the analyzed gastric adenocarcinoma samples, respectively. Positive tumor cell staining for PD-L1 or CTLA-4 was associated with inferior overall survival. Somatic mutational analysis did not reveal a correlation to expression of PD-L1 or CTLA-4 on tumor cells. Expression of PD-1 (52.2%), PD-L1 (42.2%) and CTLA-4 (1.6%) on tumor infiltrating T cells was significantly elevated compared to peripheral blood. Of note, PD-1 and PD-L1 were expressed far higher by tumor-infiltrating lymphocytes than CTLA-4. In conclusion, specific immune checkpoint-inhibitors should be evaluated in this disease and the combination with molecular targeted therapies might be of benefit. An extensive immune monitoring should accompany these studies to better understand their mode of action in the tumor microenvironment.
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne, Germany; Cologne Interventional Immunology, University of Cologne, Germany; Gastrointestinal Cancer Group Cologne, University of Cologne, Germany.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Schlößer
authors.affiliation: Institute of Pathology, University of Cologne , Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Drebber
authors.affiliation: Gastrointestinal Cancer Group Cologne, University of Cologne, Germany; Institute of Pathology, University of Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kloth
authors.affiliation: Cologne Interventional Immunology, University of Cologne , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Thelen
authors.affiliation: Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany; Department of Internal Medicine, Medical Oncology, University Hospital Basel, Switzerland.
authors.forename: Sacha I
authors.initials: SI
authors.lastname: Rothschild
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne , Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Haase
authors.affiliation: Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Garcia-Marquez
authors.affiliation: Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wennhold
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne , Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Berlth
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne , Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Urbanski
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne, Germany; Gastrointestinal Cancer Group Cologne, University of Cologne, Germany.
authors.forename: Hakan
authors.initials: H
authors.lastname: Alakus
authors.affiliation: Cluster of Excellence in Aging-Associated Disease, Core Facility Imaging, University of Cologne , Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Schauss
authors.affiliation: Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Shimabukuro-Vornhagen
authors.affiliation: Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany; Max-Planck-Institute for Metabolism Research, Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Theurich
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne , Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Warnecke-Ebertz
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne , Germany.
authors.forename: Dirk L
authors.initials: DL
authors.lastname: Stippel
authors.affiliation: Department of Internal Medicine, Medical Oncology, University Hospital Basel , Switzerland.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
authors.affiliation: Institute of Pathology, University of Cologne , Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Department of Internal Medicine I, University of Cologne , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne , Germany.
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Hölscher
authors.affiliation: Gastrointestinal Cancer Group Cologne, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zander
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne, Germany; Gastrointestinal Cancer Group Cologne, University of Cologne, Germany.
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Mönig
authors.affiliation: Cologne Interventional Immunology, University of Cologne, Germany; Department of Internal Medicine I, University of Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: von Bergwelt-Baildon
keywords: CTLA-4; Checkpoint inhibitors; PD-1; PD-L1; gastric cancer; immunotherapy; tumor-infiltrating lymphocytes