Heparin Prowess: Favorable Vascular-Immune Reprogramming in Pancreatic Cancer

Abstract

Several approaches for overcoming immunotherapy resistance in pancreatic and colorectal cancer syngeneic models were assessed using heparin and immunotherapy. Beneficial responses were attributed to heparin-induced vascular normalization, ensuing CD8+ T-cell infiltration, and M1 macrophage polarization, suggesting the potential for heparin-anchored therapies in cold tumors such as pancreatic cancer. See related article by Wei et al., p. 2525.

Figure 1.

Beneficial role of LMWH in pancreatic cancer and other cold cancers. Image on the left depicts an orthotopic Panc02 tumor in a syngeneic mouse as an example of a desert-immune tumor that is also known as a cold tumor, in which cancer-directed immune mechanisms are suppressed. The PCCs are surrounded by a desmoplastic stroma that includes CAFs that synthesize collagens, foci of necrosis, regions with micro-emboli, and coagulated blood (clots) that had leaked from the damaged tumor vasculature, M2 macrophages (Macs) that express CD206 (CD206⁺), FOXP3⁺ Treg, and a compressed vasculature that exhibits endothelial (Endo) cell damage and disorganization with loss of pericytes. The tumor was not responsive to immunotherapy and exhibited high IFP. Image on the right shows a Panc02 orthotopic tumor that had been treated with LMWH in combination with either ACT or an anti–PD-1 antibody. Both combinatorial strategies produced similar beneficial results. First and foremost, LMWH acted to normalize the tumor vasculature, with reappearance of pericytes, a decrease in IFP, normalization of the hypercoagulable state, and increased functional blood flow. Consequently, there was an influx into the tumor of CD8⁺ T cells, a decrease in Treg cells, and a switch to beneficial M1 macrophages that expressed inducible nitric oxide (iNOS⁺). In addition, there was a decrease in IFP, decreased stroma fibrosis, and impressive survival prolongation. These changes support the concept that vascular normalization with LMWH could represent a useful strategy in certain subgroups of patients with pancreatic cancer and other cold tumors and could lead to high-impact combinatorial therapies.