Neoadjuvant Therapy Remodels the Pancreatic Cancer Microenvironment via Depletion of Protumorigenic Immune Cells

Abstract Purpose: 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 neoTx-induced alterations in the pancreatic cancer microenvironment. Experimental Design: We performed the currently most comprehensive histopathologic analysis of desmoplasia, angiogenesis, neural invasion, and immune cell infiltration at the tumor–host interface of pancreatic cancer after neoTx (n = 37) versus after primary resection (n = 37) through quantitative IHC and double immunofluorescence using automated and software-based quantification algorithms. Results: We demonstrate that, independently of the applied pretreatment, neoadjuvant regimes are able to reverse the immunosuppressive behavior of malignant cells on pancreatic cancer microenvironment. Here, neoTx-driven selective depletion of regulatory T cells and myeloid-derived suppressor cells was associated with enrichment of antitumor immune cells in the peritumoral niche, decreased stromal activation, and less neural invasion. Importantly, the degree of this antitumor immune remodeling correlates to the degree of histopathologic 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 cells constitute as independent prognostic factors for neoadjuvantly treated pancreatic cancer. Conclusions: NeoTx is not only cytotoxic but has pleiotropic, beneficial effects on all cellular and noncellular components of pancreatic cancer. Combinational approaches including immunotherapy may unleash long-term and more effective antitumor responses and improve prognosis of pancreatic cancer.