Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells
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. Previ...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
China Anti-Cancer Association
2021-02-01
|
| Series: | Cancer Biology & Medicine |
| Subjects: | |
| Online Access: | http://www.cancerbiomed.org/index.php/cocr/article/view/1781 |
| _version_ | 1818461559771365376 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Arsen Osipov |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T23:48:04Z |
| format | Article |
| id | doaj.art-39e6bd391a9843878fe8179f827b11f3 |
| institution | Directory Open Access Journal |
| issn | 2095-3941 |
| language | English |
| last_indexed | 2024-12-14T23:48:04Z |
| publishDate | 2021-02-01 |
| publisher | China Anti-Cancer Association |
| record_format | Article |
| series | Cancer Biology & Medicine |
| spelling | doaj.art-39e6bd391a9843878fe8179f827b11f32022-12-21T22:43:20ZengChina Anti-Cancer AssociationCancer Biology & Medicine2095-39412021-02-0118120621410.20892/j.issn.2095-3941.2020.0273Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cellsArsen Osipov0Alex B. Blair1Juliane Liberto2Jianxin Wang3Keyu Li4Brian Herbst5Yao Xu6Shiqi Li7Nan Niu8Rufiaat Rashid9Ding Ding10Yanan Liu11Zaiqi Wang12Christopher L. Wolfgang13Richard A. Burkhart14Daniel Laheru15Lei Zheng16The Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAInxMed Shanghai, Shanghai 201202, ChinaInxMed Shanghai, Shanghai 201202, ChinaThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAThe Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USAObjective: 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.http://www.cancerbiomed.org/index.php/cocr/article/view/1781focal adhesion protein-tyrosine kinasesradiotherapypancreatic neoplasmsimmunomodulation |
| spellingShingle | 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 Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells Cancer Biology & Medicine focal adhesion protein-tyrosine kinases radiotherapy pancreatic neoplasms immunomodulation |
| title | Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells |
| title_full | Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells |
| title_fullStr | Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells |
| title_full_unstemmed | Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells |
| title_short | Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells |
| title_sort | inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through cd8 t cells |
| topic | focal adhesion protein-tyrosine kinases radiotherapy pancreatic neoplasms immunomodulation |
| url | http://www.cancerbiomed.org/index.php/cocr/article/view/1781 |
| work_keys_str_mv | AT arsenosipov inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT alexbblair inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT julianeliberto inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT jianxinwang inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT keyuli inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT brianherbst inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT yaoxu inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT shiqili inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT nanniu inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT rufiaatrashid inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT dingding inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT yananliu inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT zaiqiwang inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT christopherlwolfgang inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT richardaburkhart inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT daniellaheru inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells AT leizheng inhibitionoffocaladhesionkinaseenhancesantitumorresponseofradiationtherapyinpancreaticcancerthroughcd8tcells |