Locoregional therapies and their effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma

Table 1 Locoregional therapies and their main effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma

	Vasculature	Stroma	Immune response
Hyperthermia	Increased blood flow and vascular permeability. Recruitment of bradykinin and histamin. Increased iNOS.	Destructuration of collagen fibers. Reduction of CAF. Reduction of tumor stiffness.	Promotes APC activation. Increased infiltrating CD8+. Increased pro-inflammatory cytokines. Abscopal effect (RFA).
Radiation therapy	Reduced blood perfusion. Destructuration of microvessels with thickening vessel walls. Platelet aggregation. Microthrombus formation. Increased HIF-1 and VEGF. Increased vascular permeability.	Accumulation of extracellular matrix proteins. Increased stromal cells (fibroblasts). Thickened and stiffened tissue. Loss of hyaluronic acid. Collagen remodeling. Modification of CAF population.	Release of tumor antigens (DAMPs) ≥ APC presentation and CD8+ activation. Increased peptide availability and T cell repertoire. Release of inflammatory cytokines, CD8+, and CD4+ cells. Increased adhesion molecules (VCAM-1, ICAM-1). T cells homing. Increased PDL-1.
HIFU (mechanical effect)	Reduced blood perfusion and microvascular density.	Disruption of the collagen matrix.	Released DAMPs ≥ T cell activation. Induction of Th1 inflammation. Increased CD8+/Treg ratio.

iNOS: Inducible nitric oxide synthase; CAF: Carcinoma-associated fibroblasts; APC: Antigen presenting cell; RFA: Radiofrequency ablation; DAMPs: Damage-associated molecular patterns; HIFU: High-intensity focused ultrasound.