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Translational Therapeutics

Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer

British Journal of Cancer (2018) | Download Citation

Abstract

Background

Pancreatic cancer (PC) hijacks innate cellular processes to promote cancer growth. We hypothesized that PC exploits PD-1/PD-L1 not only to avoid immune responses, but to directly enhance growth. We also hypothesized that immune checkpoint inhibitors (ICIs) have direct cytotoxicity in PC. We sought to elucidate therapeutic targeting of PD-1/PD-L1.

Methods

PD-1 was assessed in PC cells, patient-derived organoids (PDOs), and clinical tissues. Then, PC cells were exposed to PD-L1 to evaluate proliferation. To test PD-1/PD-L1 signaling, cells were exposed to PD-L1 and MAPK was examined. Radio-immunoconjugates with anti-PD-1 drugs were developed to test uptake in patient-derived tumor xenografts (PDTXs). Next, PD-1 function was assessed by xenografting PD-1-knockdown cells. Finally, PC models were exposed to ICIs.

Results

PD-1 expression was demonstrated in PCs. PD-L1 exposure increased proliferation and activated MAPK. Imaging PDTXs revealed uptake of radio-immunoconjugates. PD-1 knockdown in vivo revealed 67% smaller volumes than controls. Finally, ICI treatment of both PDOs/PDTXs demonstrated cytotoxicity and anti-MEK1/2 combined with anti-PD-1 drugs produced highest cytotoxicity in PDOs/PDTXs.

Conclusions

Our data reveal PCs innately express PD-1 and activate druggable oncogenic pathways supporting PDAC growth. Strategies directly targeting PC with novel ICI regimens may work with adaptive immune responses for optimal cytotoxicity.

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Acknowledgments

We would like to thank Mr. Gene Pranzo and the Leo and Anne Albert Charitable Trust for their continuing support of Dr. Joseph Kim’s research studies, the Stony Brook Biobank personnel for collection of specimens, Dr. Hans Clevers and Dr. Georg Busslinger at the Hubrecht Institute for their instruction on the creation of organoids, Dr. Michael Feigin at Roswell Park Cancer Institute for his assistance with monoclonal antibodies, and Dr. Dave Tuveson and Dr. Herve Tiriac at Cold Spring Harbor Laboratory for their help with organoids. We also acknowledge the Facility for Experimental Radiopharmaceutical Manufacturing (FERM) at Stony Brook University and Dr. Peter Smith-Jones for development of our radio-immunoconjugates. Portions of the research studies were presented at the 13th Annual Academic Surgical Congress and the Scientific Forum of the American College of Surgeons Clinical Congress 2017. Funding: Study funding was provided by Stony Brook University.

Author contributions

Study concept and design: M.G., M.L., J.P., J.V., M.T., and J.K.; acquisition of data: M.G., M.L., R.A.M., C.H., J.M.B., K.S., and J.K.; analysis/interpretation of data: M.G., M.L., R.A.M., C.H., J.P., M.A.S., J.M.B., G.V.G., M.C., K.R.S., A.R.S., M.T., and J.K.; drafting of the manuscript: M.G., M.L., K.H., S.H., and J.K.; critical revision of manuscript: M.G., J.P., M.A.S., J.V., J.M.B., G.V.G., M.C., K.R.S., A.R.S., M.T., and J.K.; administrative, technical, or material support: M.L., K.H., S.H., J.V., G.V.G., A.R.S., M.T.; and final approval of manuscript: all authors.

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Affiliations

  1. Department of Surgery, University of Kentucky, Lexington, KY, USA

    • Mei Gao
    • , Miranda Lin
    •  & Joseph Kim
  2. Markey Cancer Center, University of Kentucky, Lexington, KY, USA

    • Mei Gao
    •  & Joseph Kim
  3. Department of Pathology, State University of New York, Stony Brook, NY, USA

    • Richard A. Moffitt
    •  & Kenneth R. Shroyer
  4. Department of Experimental Therapeutics, City of Hope, Duarte, CA, USA

    • Marcela A. Salazar
  5. Department of Radiology, University of Iowa, Iowa City, IA, USA

    • Jinha Park
  6. New York Cancer Specialists, East Setauket, New York, NY, USA

    • Jeffrey Vacirca
  7. Departments of Radiology, State University of New York, Stony Brook, NY, USA

    • Chuan Huang
  8. Departments of Psychiatry, State University of New York, Stony Brook, NY, USA

    • Chuan Huang
  9. Departments of Medicine, State University of New York, Stony Brook, NY, USA

    • Minsig Choi
  10. Departments of Surgery, State University of New York, Stony Brook, NY, USA

    • Georgios V. Georgakis
    • , Aaron R. Sasson
    •  & Mark A. Talamini

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Competing interests

The authors declare no competing interests.

Availability of data/materials

The corresponding author has access to all data in the study.

Ethics approval and consent to participate

Stony Brook University Institutional Review Board approved studies and informed consent was obtained from patients who provided specimens. The study was performed in accordance with the Declaration of Helsinki. Stony Brook University IACUC approved animal studies.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License.

Corresponding author

Correspondence to Joseph Kim.

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DOI

https://doi.org/10.1038/s41416-018-0298-0