Abstract 2087: AXL inhibition enhances Type 1 interferon (IFN) response and potentiates chemo-immunotherapy
Authors: Dhakal Sushil , Bougnaud Sébastien , Lorens James B. , Gausdal Gro , Moutoussamy Emmanuel E. , Gabra Hani 
Published: June 2022

Abstract
Chemotherapy elicits anti-tumor immune responses by inducing immunogenic tumor cell death, targeting suppressive immune cells and activating Type 1 interferon (IFN) responses (1, 2, 3). Chemotherapeutic agents lead to cGAS - STING cytosolic DNA sensing pathway activation that results in Type 1 IFN release (4). IFN receptor (IFNAR1, IFNAR2) signaling mimics viral immune responses, is associated with clinical benefit (5, 6) and is exploited by chemo-immunotherapies (7, 8). The receptor tyrosine kinase AXL is associated with immune evasion and immunotherapy resistance (8). AXL serves as a critical regulatory checkpoint for TLR-induced IFN responses in dendritic cells, macrophages and natural killer cells (9, 10). IFN receptor signaling induces AXL expression (11) and AXL activation on dendritic cells is targeted by viruses (e.g. Zika) to abrogate IFN responses and inhibit anti-viral immunity. AXL serves as an IFN-response checkpoint by blocking IFNAR1 and IFNAR2 signaling. We hypothesized that tumor cells exploit AXL signaling to abrogate Type 1 IFN responses and inhibit antitumor immunity. We evaluated whether AXL inhibition promotes Type 1 IFN signalling and enhances immune checkpoint inhibitor efficacy.
AXL kinase inhibition (bemcentinib) in combination with chemotherapy (doxorubicin) increased IFN response gene expression in mammary carcinoma and melanoma cell lines. In vivo, bemcentinib treatment potentiated the efficacy of immune checkpoint inhibitor treatment in combination with intratumoral doxorubicin injection (i.t) in the syngeneic myeloid derived suppressor cell (MDSC)- rich refractory mammary adenocarcinoma 4T1 model. In addition, bemcentinib treatment in conjunction with i.t. doxorubicin enhanced Type 1 IFN response, reduced cancer stemness and epithelial to mesenchymal (EMT) gene expression in this model. Furthermore, this combination treatment regimen sensitized the immune checkpoint inhibitor refractory Braf-mutant melanoma (YUMM1.7) by enhancing the type 1 IFN response resulting in significantly improved median overall survival. In conclusion, this study provides evidence that bemcentinib potentiates chemo-immunotherapy by enhancing tumor Type 1 IFN response and dampening EMT.
References: 1) Galluzzi, Can Cell 2015. 2) Yan, Front Immunol 2018. 3) Fitzgerald, Nat Immun 2003. 4) Platanias, Nature Rev Immun 2005. 5) Sistigu, Nat Med. 2014. 6) Zitvogel L, Nature Rev Immun 2015. 7) Lazzari, Ther Adv Med Onc 2018. 8) Emens, CIR 2015. 9) Aguilera, Clin Can Res 2017. 10) Rothlin, Cell 2007. 11) Huang, Eur J Immunol 2015. 12) Cruz, JCI Insight. 2019.
Citation Format: Sushil Dhakal, Sébastien Bougnaud, James B. Lorens, Gro Gausdal, Emmanuel E. Moutoussamy, Hani Gabra. AXL inhibition enhances Type 1 interferon (IFN) response and potentiates chemo-immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2087.