Abstract LB347: A lung-mimicking synthetic metastatic niche reveals N1 neutrophils drive breast cancer metastatic dormancy in the lungs

Abstract

Abstract 3D scaffolds mimicking the environment in the primary tumor or metastatic organs can deconstruct complex niche signals and facilitate the study of cancer progression and metastasis. Here, we reported that a subcutaneous 3D scaffold implant acted as a lung-mimicking dormant metastatic niche in mouse models of metastatic breast cancer, recruiting lung-tropic circulating tumor cells yet suppressing their growth through potent in situ antitumor immunity. We compared it with the immunosuppressive lungs developing lethal metastases and the dormant lungs suppressing tumor growth derived from breast cancer models with varying tumor aggressiveness and host immunity. Our data suggested that breast cancer-induced Gr1+CD11b+Ly6G+ granulocytic myeloid cells (neutrophils) infiltrated the scaffold implants and lungs, secreting the same signal to facilitate the metastatic seeding of lung-tropic cancer cells in these two types of niches. However, circulating neutrophils with opposing phenotypes and functions (N1 and N2) were selectively recruited and enriched in the dormant scaffolds/lungs and immunosuppressive lungs, respectively, responding to two distinct groups of chemoattractants. N1 or N2 neutrophils established activated or suppressive immune environments in the metastatic niches, directing different fates of cancer cells. The clinical relevance of these scientific findings was validated by the strong positive correlation of a high N1-to-N2 neutrophil chemoattractant ratio with a low-grade primary tumor, a low metastases incidence, and a better prognosis in breast cancer patients. Overall, our study revealed the multifaceted roles of neutrophils in regulating lung metastasis and underscored the importance of N1 neutrophils in driving breast cancer metastatic dormancy in the lungs, inspiring next-generation immunotherapy. Citation Format: Jing Wang, Ramon Ocadiz-Ruiz, Matthew Hall, Grace Bushnell, Sophia Orbach, Joseph Decker, Ravi Raghani, Yining Zhang, Aaron Morris, Jacqueline Jeruss, Lonnie Shea. A lung-mimicking synthetic metastatic niche reveals N1 neutrophils drive breast cancer metastatic dormancy in the lungs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB347.