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. 2016 Jul;65(7):771-8.
doi: 10.1007/s00262-016-1838-1. Epub 2016 Apr 22.

Immunobiology and immunosurveillance in patients with intraductal papillary mucinous neoplasms (IPMNs), premalignant precursors of pancreatic adenocarcinomas

Pamela L Beatty  1 , Rick van der Geest  1 , Jana G Hashash  2 , Takashi Kimura  3 , Dmitriy Gutkin  4 , Randall E Brand  2 , Olivera J Finn  5
Affiliations

Immunobiology and immunosurveillance in patients with intraductal papillary mucinous neoplasms (IPMNs), premalignant precursors of pancreatic adenocarcinomas

Pamela L Beatty et al. Cancer Immunol Immunother. 2016 Jul.

Abstract

Premalignant lesions for many cancers have been identified, and efforts are currently directed toward identification of antigens expressed on these lesions that would provide suitable targets for vaccines for cancer prevention. Intraductal papillary mucinous neoplasms (IPMNs) are premalignant pancreatic cysts of which a subset has the potential to progress to cancer. Currently, there are no validated predictive markers for progression to malignancy. We hypothesized that the presence or absence of immune surveillance of these lesions would be one such factor. Here we show that the tumor antigen MUC1, which is abnormally expressed on pancreatic cancer and is a target for cancer immunosurveillance, is also abnormally expressed on premalignant IPMN. We show that some IPMN patients make MUC1-specific IgG. Moreover, we show evidence of CD4 and CD8 T cell infiltration into IPMN areas of high dysplasia suggesting an ongoing immune response within the lesions. We also found, however, increased levels of circulating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in some IPMN patients as well as evidence of T cell exhaustion. Further studies correlating immunosurveillance or immunosuppression with IPMN progression to malignancy will help define the immune response as a biomarker of risk, leading potentially to a vaccine to boost spontaneous immunity and prevent progression to cancer.

Keywords: CITIM 2015; Cancer vaccines; IPMN; Immunosurveillance; MUC1; Pancreatic cancer.

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Conflict of interest statement

None of the authors has conflict of interest to declare.

Figures

Fig. 1
Fig. 1
MUC1 expression and T cell infiltration in IPMN. a Consecutive tissue sections are stained with antibodies directed against normal MUC1 (left panel) or hypoglycosylated tumor MUC1 (right panel). b Consecutive tissue sections are stained with antibodies directed against CD3, CD4 and CD8 showing the relationship between T cell infiltration and high-grade dysplasia, intermediate-grade dysplasia and adjacent normal epithelium
Fig. 2
Fig. 2
Anti-MUC1 IgG and levels of circulating Treg and MDSC in IPMN. a Detection by ELISA of anti-MUC1 IgG in sera of patients with IPMN and pancreatic cancer compared to healthy donor controls. Absorbance at 405 nm. b Treg as percent of CD4+ cells; c MDSC as percent of PBMC; and d levels of anti-MUC IgG correlate inversely with the levels of MDSCs in the circulation of patients with IPMN. *p < 0.01; **p < 0.05
Fig. 3
Fig. 3
Surface expression of markers of T cell exhaustion. Flow cytometry analysis of circulating T cells stained with antibodies against LAG-3, PD-1 and TIM-3. *p < 0.01; **p < 0.05
See this image and copyright information in PMC

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