Antimetastatic potential of NK cells in lung metastases across different cancer types

The seed and soil hypothesis propose that metastatic growth results from favorable interactions between disseminated tumor cells (the “seeds”) and the target organ microenvironment (the “soil”), where they must survive a hostile immune environment. Previous data in the group indicate that metastases grow in the lungs exhibit a High-Immune phenotype regardless of their primary site of origin. We hypothesize that this may reflect phenotypic plasticity in response to immunosurveillance in the lungs, and that NK cells play a relevant role in this process. To address this, expression of NK cells-related biomarkers has been interrogated in human samples. Moreover, NK cells control of metastatic growth has been tested in mouse models. Our study included an in silico cohort of tumors metastasizing in lungs such as colorectal and pancreatic cancer, and melanoma. Public transcriptomic data were used to characterize NK cell-related markers and to infer immune cell infiltration by deconvolution. The role of NK cells in lung metastasis was further evaluated using in vivo mice models, using a syngeneic bladder cancer model and a patient-derived orthoxenograft model of a colorectal cancer lung metastasis. We present new evidence indicating that the lung immune microenvironment or “immune soil” plays a crucial role in shaping the immune evasion strategies of metastatic cells, regardless of the primary tumor origin. Our data indicated that lung metastatic tumors showed significantly more NK cells infiltration than metastases in other locations, in our cohort, as well as a higher expression of HLA molecules suggesting an NK cell evasion mechanism during pulmonary colonization. Studies in mice showed that depletion of NK cells in a lung metastasis model strongly promoted pulmonary colonization, rather than in bladder and subcutaneous tumor grafts, indicating the role of NK cells in preventing lung metastasis. Finally, a proof-of-concept study supported the efficacy of NK cell-based therapy in an orthotopic model of human lung metastasis from colorectal carcinoma. NK cells in the lungs may play a determinant role in preventing metastatic growth. Metastatic tumor cells in the lung share mechanisms of evasion from NK cells. Furthermore, NK cells transfer could be a therapeutic option to treat lung metastases.