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

Mei Gao, Miranda Lin, Richard A. Moffitt, Marcela A. Salazar, Jinha Park, Jeffrey Vacirca, Chuan Huang, Kenneth R. Shroyer, Minsig Choi, Georgios V. Georgakis, Aaron R. Sasson, Mark A. Talamini, Joseph Kim

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish
Pages (from-to)88-96
Number of pages9
JournalBritish Journal of Cancer
Volume120
Issue number1
DOIs
StatePublished - Jan 8 2019

Bibliographical note

Publisher Copyright:
© 2018, Cancer Research UK.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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