Schloesser, Hans A., Drebber, Uta, Kloth, Michael, Thelen, Martin ORCID: 0000-0002-2785-9726, Rothschild, Sacha I., Haase, Simon, Garcia-Marquez, Maria, Wennhold, Kerstin ORCID: 0000-0001-5539-7226, Berlth, Felix ORCID: 0000-0002-3780-0728, Urbanski, Alexander, Alakus, Hakan, Schauss, Astrid, Shimabukuro-Vornhagen, Alexander, Theurich, Sebastian ORCID: 0000-0001-5706-8258, Warnecke-Ebertz, Ute, Stippel, Dirk L., Zippelius, Alfred, Buettner, Reinhard, Hallek, Michael, Hoelscher, Arnulf H., Zander, Thomas, Moenig, Stefan P. and von Bergwelt-Baildon, Michael (2016). Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma. OncoImmunology, 5 (5). PHILADELPHIA: TAYLOR & FRANCIS INC. ISSN 2162-402X

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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. PDL1 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schloesser, Hans A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Drebber, UtaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloth, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thelen, MartinUNSPECIFIEDorcid.org/0000-0002-2785-9726UNSPECIFIED
Rothschild, Sacha I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haase, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Marquez, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wennhold, KerstinUNSPECIFIEDorcid.org/0000-0001-5539-7226UNSPECIFIED
Berlth, FelixUNSPECIFIEDorcid.org/0000-0002-3780-0728UNSPECIFIED
Urbanski, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alakus, HakanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schauss, AstridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shimabukuro-Vornhagen, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Theurich, SebastianUNSPECIFIEDorcid.org/0000-0001-5706-8258UNSPECIFIED
Warnecke-Ebertz, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stippel, Dirk L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zippelius, AlfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelscher, Arnulf H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moenig, Stefan P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Bergwelt-Baildon, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-289659
DOI: 10.1080/2162402X.2015.1100789
Journal or Publication Title: OncoImmunology
Volume: 5
Number: 5
Date: 2016
Publisher: TAYLOR & FRANCIS INC
Place of Publication: PHILADELPHIA
ISSN: 2162-402X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RENAL-CELL CARCINOMA; PROGNOSTIC IMPLICATIONS; CLINICAL-SIGNIFICANCE; ANTI-PD-1 ANTIBODY; ADVERSE PROGNOSIS; CANCER; PD-1; BLOCKADE; THERAPY; TUMORSMultiple languages
Oncology; ImmunologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28965

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