Human splenic TER cells: A relevant prognostic factor acting via the artemin‐GFRα3‐ERK pathway in pancreatic ductal adenocarcinoma

Abstract

Splenectomy is routinely performed during distal or total pancreatectomy (DP or TP) for pancreatic ductal adenocarcinoma (PDAC), but information about its oncological value is limited. TER cells, nonimmune cells discovered in the spleens of tumour‐bearing mice, are elicited by tumours and promote tumour progression, while their role in the clinical outcomes of patients with PDAC remains unclear. In our study, postoperative specimens from 622 patients who underwent DP or TP with splenectomy were analysed by flow cytometry or immunofluorescence, and the relationship between splenic TER cell count and clinical parameters was calculated. We also purified human TER cells for functional experiments and mechanistic studies. We found that TER cell numbers were increased only in the spleens of patients with PDAC but not in PDAC tissue and adjacent pancreatic tissue. High splenic TER cell counts independently predicted poor prognosis (P < .001) and indicated large tumour size, lymph node metastasis, advanced 8th AJCC/mAJCC stage and high CA19‐9 classification (all P < .050) in patients with PDAC. Mechanistic analysis showed that TER cells express artemin, which facilitates the proliferation and invasion of PDAC cells by activating GFRα3‐ERK signalling. Our study reveals that TER cell count is an indicator of poor prognosis of PDAC, while splenectomy during pancreatic surgery might provide oncological benefits in addition to ensuring the radical resection of PDAC.

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

“…The physiological role of artemin involves the regulation of neuronal survival, maintenance, and differentiation [ 120 ]. Artemin also has protumorigenic activity and promotes cancer cell survival, proliferation, migration, and invasiveness [ 62 , 121 , 122 , 123 ]. In murine models, it promotes tumor growth and accelerates disease progression [ 62 ].…”

“…Thus, the reduction in EPC expansion reduces the increase in the artemin concentration in the serum and decreases tumor growth [ 62 ]. Artemin-expressing CD45 − EPCs were also detected in the spleens of patients with hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) [ 62 , 123 ], which suggests their role in cancer patients.…”

“…Moreover, these differences are also manifested by their localization. While immunomodulatory early-stage EPCs accumulate in the spleen and intensively infiltrate TME, tumor-promoting late-stage EPCs are detected mainly in the spleen where they secrete artemin into circulation [ 41 , 42 , 62 , 123 ]. Collectively, early-stage and late-stage EPCs differ substantially regarding their gene expression profile, level of immunomodulatory mediators, and their role in promoting cancer progression ( Table 5 ).…”

“…In tumor-bearing mice, EPCs expand during tumor progression in many extramedullary organs ( Table 6 ), predominantly the spleen, liver, and peripheral blood, as well as infiltrate tumors [ 41 , 43 , 62 ]. In humans, EPCs were detected in the spleen, TME, and peripheral blood of cancer patients [ 41 , 62 , 123 , 131 ]. In general, anemia severity correlates with the frequency of EPCs [ 41 ].…”

“…Late-stage EPCs promote tumor growth and invasiveness via the secretion of artemin [ 62 , 123 ]. Anti-artemin neutralizing antibody inhibits tumor growth and increases the survival of tumor-bearing mice [ 62 ].…”