Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival
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Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival. / Karstens, Karl-Frederick; Kempski, Jan; Giannou, Anastasios D; Pelczar, Penelope; Steglich, Babett; Steurer, Stefan; Freiwald, Eric; Woestemeier, Anna; Konczalla, Leonie; Tachezy, Michael; Reeh, Matthias; Bockhorn, Maximilian; Perez, Daniel; Mann, Oliver; Lohse, Ansgar W; Roesch, Thomas; Izbicki, Jakob R; Gagliani, Nicola; Huber, Samuel.
In: CANCER IMMUNOL IMMUN, Vol. 69, No. 6, 06.2020, p. 1043-1056.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival
AU - Karstens, Karl-Frederick
AU - Kempski, Jan
AU - Giannou, Anastasios D
AU - Pelczar, Penelope
AU - Steglich, Babett
AU - Steurer, Stefan
AU - Freiwald, Eric
AU - Woestemeier, Anna
AU - Konczalla, Leonie
AU - Tachezy, Michael
AU - Reeh, Matthias
AU - Bockhorn, Maximilian
AU - Perez, Daniel
AU - Mann, Oliver
AU - Lohse, Ansgar W
AU - Roesch, Thomas
AU - Izbicki, Jakob R
AU - Gagliani, Nicola
AU - Huber, Samuel
PY - 2020/6
Y1 - 2020/6
N2 - OBJECTIVE: Reflux promotes esophageal adenocarcinomas (EACs) creating a chronic inflammatory environment. Survival rates are low due to early local recurrences and distant metastasis. Hence, there is a need for new potential treatment options like immunotherapies. However, the inflammatory microenvironment in EACs and its impact on patient outcome remain to be fully understood.METHODS: mRNA expression levels of pro- and anti-inflammatory markers in 39 EAC patients without neoadjuvant radio-chemotherapy were measured. Data were confirmed using flow cytometric analysis of freshly resected surgical specimens. Inflammatory alterations in premalignant lesions of Barrett's esophagus were analyzed by immunohistochemistry.RESULTS: Expression levels of IL22 were reduced in EAC, while expression levels of FOXP3, IL10 and CTLA4 were increased. Flow cytometry demonstrated a strong infiltration of CD4+ T cells with a reduction in CD4+ T cells producing IL-22 or IL-17A. We also observed an increase in CD4+CD127lowFOXP3+ cells producing IL-10. Accumulation of FOXP3+ T cells occurred prior to malignant changes. High expression of IL10 and low expression of IL22 in EAC were associated with reduced overall survival. Moreover, increased expression of IL10, CTLA4 and PD1 in the unaltered esophageal mucosa distant to the EAC was also linked with an unfavorable prognosis.CONCLUSION: EAC shows an anti-inflammatory environment, which strongly affects patient survival. The microscopically unaltered peritumoral tissue shows a similar anti-inflammatory pattern indicating an immunological field effect, which might contribute to early local recurrences despite radical resection. These data suggest that using checkpoint inhibitors targeting anti-inflammatory T cells would be a promising therapeutic strategy in EAC.
AB - OBJECTIVE: Reflux promotes esophageal adenocarcinomas (EACs) creating a chronic inflammatory environment. Survival rates are low due to early local recurrences and distant metastasis. Hence, there is a need for new potential treatment options like immunotherapies. However, the inflammatory microenvironment in EACs and its impact on patient outcome remain to be fully understood.METHODS: mRNA expression levels of pro- and anti-inflammatory markers in 39 EAC patients without neoadjuvant radio-chemotherapy were measured. Data were confirmed using flow cytometric analysis of freshly resected surgical specimens. Inflammatory alterations in premalignant lesions of Barrett's esophagus were analyzed by immunohistochemistry.RESULTS: Expression levels of IL22 were reduced in EAC, while expression levels of FOXP3, IL10 and CTLA4 were increased. Flow cytometry demonstrated a strong infiltration of CD4+ T cells with a reduction in CD4+ T cells producing IL-22 or IL-17A. We also observed an increase in CD4+CD127lowFOXP3+ cells producing IL-10. Accumulation of FOXP3+ T cells occurred prior to malignant changes. High expression of IL10 and low expression of IL22 in EAC were associated with reduced overall survival. Moreover, increased expression of IL10, CTLA4 and PD1 in the unaltered esophageal mucosa distant to the EAC was also linked with an unfavorable prognosis.CONCLUSION: EAC shows an anti-inflammatory environment, which strongly affects patient survival. The microscopically unaltered peritumoral tissue shows a similar anti-inflammatory pattern indicating an immunological field effect, which might contribute to early local recurrences despite radical resection. These data suggest that using checkpoint inhibitors targeting anti-inflammatory T cells would be a promising therapeutic strategy in EAC.
U2 - 10.1007/s00262-020-02517-8
DO - 10.1007/s00262-020-02517-8
M3 - SCORING: Journal article
C2 - 32100077
VL - 69
SP - 1043
EP - 1056
JO - CANCER IMMUNOL IMMUN
JF - CANCER IMMUNOL IMMUN
SN - 0340-7004
IS - 6
ER -