Prognostic role of the tumour microenvironment in esophago-gastric, pancreatic and periampullary adenocarcinoma: B cells and beyond

Sammanfattning: Cancer development depends on cells aquiring a skillset of limitless growth and finally invasive properties to allow for metastasis, as summarised by the six hallmarks of cancer. Recently four more hallmarks have been added: genomic instability, deregulating cellular metabolism, tumour-promoting inflammation and avoiding immune destruction. This thesis focuses on the latter two: immune system and cancer cell interactions. Oesophageal and gastric cancer present late and only 25% and 30%, respectively, will be subjected to curative treatment. Periampullary cancer includes: pancreatic cancer (PDA), biliary, ampullary and duodenal cancer. Periampullary cancer is often dichotomised into intestinal (I)-type and pancreatobiliary (PB)-type. Overall survival for PDA is 5%, whilst I-type periampullary cancer has a better prognosis.The aim of this thesis was to analyse the expression of the polymeric immunoglobulin receptor (pIgR), and the abundance of B cells and plasma cells in oesophago-gastric, pancreatic and periampullary adenocarcinoma, and to explore their potential prognostic and predictive value.To this end, two patient cohorts were used The first cohort encompassed 174 patients with surgically resected oesophago-gastric adenocarcinoma, who had not received neoadjuvant treatment. The second cohort encompassed 175 patients treated with pancreatoduodenectomy for pancreatic and periampullary adenocarcinoma. Tissue microarrays were constructed from primary tumours and selected metastases and immunohistochemistry (IHC) was applied with validated antibodies against pIgR, CD20+ B cells, CD138+ and IGKC+ plasma cells. Light microscopy and/or digital image analysis was used for detection. In addition, PIGR gene expression was assessed by quantitative polymerase chain reaction. High expression of pIgR, a transporter protein that transcytoses antibodies across epithelial cells to mucosal surfaces and has been associated with improved survival in many cancer types, was associated with a prolonged time to recurrence (TTR) and overall survival (OS) in oesophageal and gastric junction adenocarcinoma. Furthermore, reduced expression of pIgR was associated with decreased OS in I-type periampullary adenocarcinoma. In oesophageal and gastric adenocarcinoma, high density of IGKC+ plasma cells was associated with a prolonged TTR and OS. No association was seen for IGKC+ plasma cells in I-type or PB-type periampullary adenocarcinoma but a, high density of CD20+ B cells was associated with both a prolonged TTR and OS. In addition, there was a significant treatment interaction in relation to OS between high density of CD20+ B cells and adjuvant chemotherapy in patients with PB-type periampullary adenocarcinoma. In conclusion, high pIgR expression is associated with improved outcomes in oesophageal, GE junction and I-type periampullary adenocarcinoma. IGKC+ plasma cells are associated with a prolonged survival in esophageal and gastric adenocarcinoma. CD20+ B cells are associated with a prolonged survival in I-type and PB-type periampullary adenocarcinoma, and, possibly, with an improved response to adjuvant chemotherapy in PB-type tumours. The underlying mechanistic principles remain to be deciphered.