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

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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.

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Abbreviations

CTL:

Cytotoxic T cell

IFN-g:

Interferon gamma

IL-4:

Interleukin-4

IPMN:

Intraductal papillary mucinous neoplasm(s)

LAG-3:

Lymphocyte-activated gene-3

MDSC:

Myeloid-derived suppressor cell

MUC1:

Mucin 1

PBMC:

Peripheral blood mononuclear cell

PD-1:

Programed cell death protein-1

TIM-3:

T cell immunoglobulin and mucin-containing protein-3

Treg:

Regulatory T cell

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Acknowledgments

We thank Dr. Aatur Singhi for providing IPMN tissue for immunohistochemistry and Dr. John McKolanis for help with ELISA. This work was supported by the National Institute of Health Grant CA168392-05 (Finn) and the University of Pittsburgh CTSI Grant # 5UL1TR000005 (Finn and Brand).

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    Authors and Affiliations

    1. Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, E1040 BST, Pittsburgh, PA, 15261, USA

      Pamela L. Beatty, Rick van der Geest & Olivera J. Finn

    2. Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

      Jana G. Hashash & Randall E. Brand

    3. Department of Regenerative Surgery, Fukushima Medical University, Fukushima, Japan

      Takashi Kimura

    4. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

      Dmitriy Gutkin

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    1. Pamela L. Beatty
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    Correspondence to Olivera J. Finn.

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    Pamela L. Beatty and Rick van der Geest have contributed equally to this work.

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    Beatty, P.L., van der Geest, R., Hashash, J.G. et al. Immunobiology and immunosurveillance in patients with intraductal papillary mucinous neoplasms (IPMNs), premalignant precursors of pancreatic adenocarcinomas. Cancer Immunol Immunother 65, 771–778 (2016). https://doi.org/10.1007/s00262-016-1838-1

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