title: Expression pattern of immune suppressive cytokines and growth factors in oesophageal adenocarcinoma reveal a tumour immune escape-promoting microenvironment.
abstract: Immunotherapy for solid cancers, such as oesophageal adenocarcinoma (OAC), is generally hampered by an unfavourable immunological tumour microenvironment. This prompted us to investigate the nature of the OAC environment. Biopsies of tumour and normal control tissues were collected from 17 OAC patients, and investigated using fluorescent immunohistochemistry (IHC) for the expression of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), transforming growth factor-beta, indoleamine 2-3 dioxygenase, CXCL3 and CXCR1, and for measuring a panel of cytokines by cytometric bead array (CBA), and for Granzyme B (GrB), Perforin and PI9 detection by semi-quantitative PCR (QPCR). IHC showed that expression of all the above-mentioned factors is upregulated in 80-93% of the tumours. By QPCR, the cytokine interleukin (IL)-8 was significantly upregulated in tumour samples (P < 0.05). IL-6, IL-10, GrB and Perforin did not show any significant difference between normal and tumour samples, whereas PI9 levels were significantly higher in normal when compared with the tumour samples. CBA confirmed upregulation of IL-8 and show upregulation of IL-1beta in the tumours (P < 0.05). Regarding IL-6 and interferon (IFN)-gamma, no significant differences were observed between normal and tumour tissues. The OAC microenvironment is characterized by a lack of cytokines and factors that normally would enhance anti-cancer responses, such as IFN-gamma and GrB, and by a high expression of several immuno-suppressive factors, such as COX-2, VEGF and IL-8. For future improvement of treatment efficacy of OAC patients, it will be of importance to combine immunotherapy with immune-modulating agents.
authors.affiliation: Department of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. f.milano@amc.uva.nl
authors.forename: F
authors.initials: F
authors.lastname: Milano
authors.forename: T
authors.initials: T
authors.lastname: Jorritsma
authors.forename: A M
authors.initials: AM
authors.lastname: Rygiel
authors.forename: J J
authors.initials: JJ
authors.lastname: Bergman
authors.forename: C
authors.initials: C
authors.lastname: Sondermeijer
authors.forename: A
authors.initials: A
authors.lastname: Ten Brinke
authors.forename: S M
authors.initials: SM
authors.lastname: vanHam
authors.forename: K K
authors.initials: KK
authors.lastname: Krishnadath
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D012313:RNA / Q000235:genetics; D019139:Tumor Escape; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; D012313:RNA; D051546:Cyclooxygenase 2