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CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer

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Abstract

The ability of some tumors to exclude effector T cells represents a major challenge to immunotherapy. T cell exclusion is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a disease where blockade of the immune checkpoint molecule CTLA-4 has not produced significant clinical activity. In PDAC, effector T cells are often scarce within tumor tissue and confined to peritumoral lymph nodes and lymphoid aggregates. We hypothesized that CTLA-4 blockade, despite a lack of clinical efficacy seen thus far in PDAC, might still alter T cell immunobiology, which would have therapeutic implications. Using clinically relevant genetic models of PDAC, we found that regulatory T cells (Tregs), which constitutively express CTLA-4, accumulate early during tumor development but are largely confined to peritumoral lymph nodes during disease progression. Tregs were observed to regulate CD4+, but not CD8+, T cell infiltration into tumors through a CTLA-4/CD80 dependent mechanism. Disrupting CTLA-4 interaction with CD80 was sufficient to induce CD4 T cell infiltration into tumors. These data have important implications for T cell immunotherapy in PDAC and demonstrate a novel role for CTLA-4/CD80 interactions in regulating T cell exclusion. In addition, our findings suggest distinct mechanisms govern CD4+ and CD8+ T cell infiltration in PDAC.

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Abbreviations

CiMist1 :

Mist1CreERT2

CTLA-4:

Cytotoxic lymphocyte-associated antigen-4

DAB:

3,3′-Diaminobenzidine

DC:

Dendritic cell

KCiMist1 :

Mist1CreERT2;LSL-Kras G12D/+

KPC:

LSL-Kras G12D/+;LSL-Trp53 R172H/+; Pdx-1Cre

PanIN:

Pancreatic intraepithelial neoplasia

PC:

LSL-Trp53 R172H/+;Pdx-1Cre

PDAC:

Pancreatic ductal adenocarcinoma

Treg:

Regulatory T cell

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Acknowledgements

The authors thank Patrick Guirnalda for helpful discussion and Adam Bedenbaugh for advice and technical assistance with immunohistochemistry assays.

Author information

Author notes

  1. Fee Bengsch and Dawson M. Knoblock contributed equally to this work.

Authors and Affiliations

  1. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    Fee Bengsch, Dawson M. Knoblock, Anni Liu & Gregory L. Beatty

  2. Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Fee Bengsch, Dawson M. Knoblock, Anni Liu & Gregory L. Beatty

  3. Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Florencia McAllister

  4. Perelman Center for Advanced Medicine, South Pavilion, Room 8-107, 3400 Civic Center Blvd. Bldg 421, Philadelphia, PA, 19104-5156, USA

    Gregory L. Beatty

Authors
  1. Fee Bengsch
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  2. Dawson M. Knoblock
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  3. Anni Liu
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  4. Florencia McAllister
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  5. Gregory L. Beatty
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Corresponding author

Correspondence to Gregory L. Beatty.

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Financial support

Support for this project was provided by the following grants from the National Institutes of Health and National Cancer Institute: K08 CA138907 (Gregory L. Beatty) and R01 CA197916 (Gregory L. Beatty). We are grateful to the Molecular Biology and Molecular Pathology and Imaging Cores of the Penn Center supported by a Molecular Studies in Digestive and Liver Diseases grant from the National Institutes of Health. This work was also supported by the following foundations and agencies: AACR-PanCAN Career Development Award (Florencia McAllister), National Pancreas Foundation (Florencia McAllister), Department of Defense Discovery Award (Gregory Beatty), and the Damon Runyon Cancer Research Foundation Innovation Award supported by the Nadia’s Gift Foundation (Gregory Beatty).

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The authors declare that they have no conflict of interest.

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Bengsch, F., Knoblock, D.M., Liu, A. et al. CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer. Cancer Immunol Immunother 66, 1609–1617 (2017). https://doi.org/10.1007/s00262-017-2053-4

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  • DOI: https://doi.org/10.1007/s00262-017-2053-4

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