Abstract 1623: AXL-STAT3 targeting of lung tumor microenvironments

Dynamic tumor microenvironments contain a myriad of cell subtypes, each providing a unique functionality in support of malignant growth. To prepare a metastatic niche, a tight network must be present to coordinate the delivery and sharing of co-stimulatory signals among malignant tumor epithelial cells and supportive host cells. AXL and STAT3 cascades are critical components of intracellular signaling networks, as they translate multiple external stimuli into specific cellular responses. Single cell profiling of lung tumors reveals that AXL collaborates with STAT3 to create a unified tumor ecosystem favoring hybrid epithelial-to-mesenchymal transition states of lung epithelial cells, pro-tumorigenic remodeling of fibroblasts and M2 polarization of macrophages. Disruption of AXL-STAT3 circuit with AXL inhibitor and JAK inhibitor not only compromises this co-dependency in A549 lung cancer cells implanted in xenograft mice, but also limits their ability to conscript murine fibroblasts, macrophages and other immune cells that form a symbiotic community for tumor growth. Our preclinical work suggests that combined targeting of AXL-STAT3 circuit could disturb the communication among diverse cell subtypes in the lung tumor microenvironment, thus limiting the metastatic progression. Our co-culture studies reveal that AXL signaling in lung cancer cells and fibroblasts exerts an IL-11 mediated paracrine effect on macrophages to sustain STAT3 signaling for M2 polarization and cancer stemness mimicry. In vivo drug testing in A549 mouse xenograft model demonstrate that AXL-STAT3 inhibition leads to reduction in host cell recruitment and attenuates M2 polarization of macrophages and pro-tumorigenic remodeling of stromal fibroblasts. AXL-STAT3 targeting to dismantle lung tumor microenvironments is a promising therapeutic strategy and may establish new treatment paradigms for patients with lung adenocarcinoma.

Citation Format: Josephine Amalia Taverna, Chia-Nung Hung, Meizhen Chen, Joel Michalek, Chun-Liang Chen, Nameer Kirma, Chih-Wei Chou, Xi Tan, Chiou-Miin Wang, Zhang Zhao, Duy Nguyen, Daniel DeArmond, Tim Huang. AXL-STAT3 targeting of lung tumor microenvironments [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 1623.