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Original Article | Open Access

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

Arsen Osipov1,2,3, Alex B. Blair1,2,4, Juliane Liberto1,2,3, Jianxin Wang1,2,3, Keyu Li1,2,3, Brian Herbst1,2,3, Yao Xu1,2,3, Shiqi Li1,2,3, Nan Niu1,2,3, Rufiaat Rashid1,2,3, Ding Ding1,2,4, Yanan Liu5, Zaiqi Wang5, Christopher L. Wolfgang1,2,3,4, Richard A. Burkhart1,2,3,4, Daniel Laheru1,2,3,4, Lei Zheng1,2,3,4 ( )
The Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USA
The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USA
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USA
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USA
InxMed Shanghai, Shanghai 201202, China
Show Author Information

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.

Keywords

immunomodulationradiotherapyFocal adhesion protein-tyrosine kinasespancreatic neoplasms

Electronic Supplementary Material

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cbm-18-1-206_ESM.pdf (150.8 KB)

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Cancer Biology & Medicine
Volume 18 Issue 1,
February 2021
Pages 206-214
DOI: 10.20892/j.issn.2095-3941.2020.0273
Cite this article:
Osipov A, Blair AB, Liberto J, et al. Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells. Cancer Biology & Medicine, 2021, 18(1): 206-214. https://doi.org/10.20892/j.issn.2095-3941.2020.0273

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Received: 06 June 2020
Accepted: 29 October 2020
Published: 01 February 2021
©2021 Cancer Biology & Medicine.

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