NOD mice, susceptible to pancreatic autoimmunity, demonstrate delayed growth of pancreatic cancer.

James Dooley,Yulia Lampi,Adrian Liston,Uwe Himmelreich,Tom Dresselaers,Emanuela Pasciuto,Vasiliki Lagou

doi:10.18632/oncotarget.21261

Abstract

Pancreatic cancer is a high mortality form of cancer, with a median survival only six months. There are multiple associated risk factors associated, most importantly type 2 diabetes, obesity, pancreatitis and smoking. The relative rarity of the disease, however, has made it difficult to dissect causative risk factors, especially with related risk factors. A major unanswered question with important therapeutic implications is the effect of immunological responses on pancreatic cancer formation, with data from other cancers suggesting the potential for local immunological responses to either increase cancer development or increase cancer elimination. Due to the rarity and late diagnosis of pancreatic cancer direct epidemiological evidence is lacking, thus necessitating a reliance on animal models. Here we investigated the relationship between pancreatic autoimmunity and cancer by backcrossing the well characterised Ela1-Tag transgenic model of pancreatic cancer onto the pancreatic autoimmune susceptible NOD mouse strain. Through longitudinal magnetic resonance imaging we found that the NOD genetic background delayed the onset of pancreatic tumours and substantially slowed the growth rate of tumours after development. These results suggest that elevated autoimmune surveillance of the pancreas limits tumour formation and growth, identifying pancreatic cancer as a promising target for immune checkpoint blockade therapies that unleash latent autoimmunity.

Highlights

Pancreatic cancer is a relatively rare form of cancer, the high fatality rate makes it the fourth highest cancer in the absolute number of fatalities [1]
In order to determine the impact of genetic susceptibility to pancreatic autoimmunity, we backcrossed the T antigen (TAg)+ transgenic strain to the NOD background for more than 14 generations
Despite the genetic background predisposed to pancreatic autoimmunity, none of the NOD mice developed autoimmune diabetes (Supplementary Figure 1), due to the conventional housing required for magnetic resonance imaging (MRI) analysis

Summary

Introduction

Pancreatic cancer is a relatively rare form of cancer, the high fatality rate makes it the fourth highest cancer in the absolute number of fatalities [1]. Cancer cells are “self”, giving the anti-self response of autoimmune T cells and B cells the potential to actively eradicate developing cancers [8] This potential activity of autoimmunity as a protective factor is suggested by the improved rate of melanoma clearance in patients with autoimmune vitiligo, where autoimmune T cells infiltrate into the skin [9, 10]. While NOD mice are classically identified with autoimmunity towards the endocrine tissue of the pancreas, the strain is intrinsically prone to the development of autoimmunity towards the exocrine tissue, with an increase in the number of circulating autoreactive T cells and heightened traffic through the pancreas, which can be tipped towards pathogenic outcomes through genetic manipulation [12,13,14]. Using the Ela1-TAg transgenic model, we find that NOD mice display delayed formation of pancreatic cancer and substantially slower tumour growth rates, suggesting that elevated autoreactivity limits local cancer development and growth

Methods

Results

Conclusion