Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells

Arsen Osipov, Alex B. Blair, Juliane Liberto, Jianxin Wang, Keyu Li, Brian Herbst, Yao Xu, Shiqi Li, Nan Niu, Rufiaat Rashid, Ding Ding, Yanan Liu, Zaiqi Wang, Christopher L. Wolfgang, Richard A. Burkhart, Daniel Laheru, Lei Zheng

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy, due in large part to its resistance to conventional therapies, including radiotherapy (RT). Despite RT exerting a modest antitumor response, it has also been shown to promote an immunosuppressive tumor microenvironment. Previous studies demonstrated that focal adhesion kinase inhibitors (FAKi) in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory (T regs) cells, and subsequently enhance effector T cell infiltration. FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies. Thus, we investigated the impact of FAK inhibition on RT, its potential as an RT sensitizer and immunomodulator in a murine model of PDAC. Methods: We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT. Results: In this study we showed that IN10018, a small molecular FAKi, enhanced antitumor response to RT. Antitumor activity of the combination of FAKi and RT is T cell dependent. FAKi in combination with RT enhanced CD8+ T cell infiltration significantly in comparison to the radiation or FAKi treatment alone (P < 0.05). FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone (P < 0.01). Conclusions: These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.

Original languageEnglish (US)
Pages (from-to)206-214
Number of pages9
JournalCancer Biology and Medicine
Volume18
Issue number1
DOIs
StatePublished - Feb 2021

Keywords

  • Focal adhesion protein-tyrosine kinases
  • Immunomodulation
  • Pancreatic neoplasms
  • Radiotherapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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