Role of respiratory viral infections and inflammation in promoting metastatic outgrowth in the lung

The leading cause of breast cancer deaths is metastasis. Metastatic relapse can occur months to years after the initial diagnosis and treatment of the primary tumor. Cancer cells can disseminate from the primary tumor into different tissues including lungs and remain in a dormant state for years to decades. Awakening of these dormant disseminated cancer cells (DCC) leads to metastasis. Finding factors that trigger the awakening of dormant DCC and developing strategies to reduce the risk of awakening is therefore an unmet need. While it is known that inflammation is a key contributing factor to the awakening of dormant DCC, no studies have investigated whether inflammation triggered by viral respiratory infections (a very common infection worldwide) in the lung can promote the expansion of DCC and lead to the development of metastases. Our recent studies using a mouse model of breast cancer DCC dormancy in the lung have revealed a dramatic increase in DCC awakening and expansion in the lungs following influenza virus infection. Our data support the hypothesis that respiratory viral infections can promote DCC awakening and expansion through two phases: first, through IL-6 dependent DCC awakening and expansion, and second, CD4 T-cell mediated protection from elimination (in part by CD8 cells). We further show that infection with a mouse-adapted SARS-CoV-2 promotes a similar awakening and expansion of DCC in mice. Finally, epidemiological studies reveal how prior infection with SARS-CoV-2 infection increases metastatic progression in lungs and cancer- related deaths for cancer survivors. We propose to determine mechanisms by which acute respiratory viral infections induce the awakening of dormant DCC leading to metastatic disease, whether and how such infections can prime DCC for activation by subsequent exposures, and how CD4 and CD8 cells differentially control the persistence of expanded DCC during influenza virus infection. Impact: Proposed studies to understand how different pulmonary viral infections alter DCC dormancy and host immune responses, to determine the consequences for progression to metastatic disease, and to explore underlying mechanisms, should yield valuable and actionable insight into the key cell types and molecular mediators, informing early detection and prevention strategies for at-risk individuals.