Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells.
2021
Objective: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy, due in large part to its resistance to conventionaltherapies, including radiotherapy (RT). Despite RT exerting a modest antitumor response, it has also been shown to promote animmunosuppressive tumor microenvironment. Previous studies demonstrated that focal adhesion kinase inhibitors (FAKi) inclinical development inhibit the infiltration of suppressive myeloid cells and T regulatory (T regs) cells, and subsequently enhanceeffector T cell infiltration. FAK inhibitors in clinical development have not been investigated in combination with RT in preclinicalmurine models or clinical studies. Thus, we investigated the impact of FAK inhibition on RT, its potential as an RT sensitizer andimmunomodulator 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 ofthe combination of FAKi and RT is T cell dependent. FAKi in combination with RT enhanced CD8+ T cell infiltration significantlyin comparison to the radiation or FAKi treatment alone (P < 0.05). FAKi in combination with radiation inhibited the infiltrationof 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 toprime the tumor microenvironment of PDAC for immunotherapy.
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