Neoadjuvant therapy remodels the pancreatic cancer microenvironment via depletion of pro-tumorigenic immune cells

Mota Reyes, C., Teller, S., Muckenhuber, A., Konukiewitz, B., Safak, O., Weichert, W., Friess, H., Ceyhan, G. O., and Demir, I. E. (2020). Clin Cancer Res 26, 220-231. doi: 10.1158/1078-0432.CCR-19-1864


Neoadjuvant therapy (neoTx) has dramatically improved the prognosis of patients with locally advanced and borderline resectable pancreatic ductal adenocarcinoma, yet its mechanisms of action on tumor cells and the tumor microenvironment are still unknown. Here, we aimed to characterize the multiple facets of neoadjuvant therapy-induced alterations in the pancreatic cancer (PCa) microenvironment.

We performed the currently most comprehensive histopathological analysis of desmoplasia, angiogenesis, neural invasion and immune cell infiltration at the tumour-host interface of PCa after neoTx (n=37) vs. after primary resection (n=37) through quantitative immunohistochemistry and double immunofluorescence using automated and software-based quantification algorithms.

We demonstrate that, independently of the applied pre-treatment, neoadjuvant regimes are able to reverse the immunosuppressive behavior of malignant cells on PCa microenvironment. Here, neoTx-driven selective depletion of Tregs and myeloid derived suppressor cells (MDSC) was associated with enrichment of anti-tumor immune cells in the peritumoral niche, decreased stromal activation, and less neural invasion. Importantly, the degree of this anti-tumor immune remodeling correlates to the degree of histopathological response to neoTx. Survival analysis revealed that the tumor proliferation rate together with the activation of the stroma and the intratumoral infiltration with CD4+ T cells and natural killer (NK) cells constitute as independent prognostic factors for neoadjuvantly treated PCa.

NeoTx is not only cytotoxic, but has pleiotropic, beneficial effects on all cellular and non-cellular components of PCa. Combinational approaches including immunotherapy may unleash long-term and more effective anti-tumor responses and improve prognosis of PCa.