Abstract B021: Influenza-induced inflammatory response reactivates and promotes dormant breast cancer cell outgrowth in lungs
Authors: Johnson Bryan J. , Chia Shi Biao , Zaberezhnyy Vadym , Sreekanth Varsha , Boorgula Meher , Papanicolaou Michael , Costello James , Goodspeed Andrew , Aguirre-Ghiso Julio A. , Rincon Mercedes , DeGregori James V. 
Published: February 2024

Abstract
Breast cancer is the most common form of cancer and the second cancer-causing death in females. Although remission rates are high if detected early, survival rates drop substantially when breast cancer becomes metastatic. Metastatic relapse can occur months to years after the initial diagnosis and treatment of the primary tumor. This relapse is mediated by awakening of dormant disseminated cancer cells (dDCCs). Studies have demonstrated that the relationship between the microenvironment and dDCCs is critical for maintaining both dormancy and for facilitating awakening to promote metastasis development. Prior studies have shown increased inflammation in the microenvironment can facilitate DCC awakening and outgrowth. Viral respiratory infections are also associated with massive inflammation and immune cell influx, typically in acute form. Respiratory infections affect millions of people worldwide, as is particularly evident in the ongoing SARS-CoV2 pandemic and variably severe annual influenza seasons. How the inflammatory response to viral respiratory infections impacts breast cancer metastasis remains unclear. Using FVB MMTV-erbB2/neu/HER2 mice as a model of breast dormancy in the lungs and influenza virus, we show that following influenza infection there is a significant increase in the number of disseminated cancer cells in the lungs of influenza infected mice with more than a 1000-fold expansion of carcinoma cells over a couple of weeks. Interestingly most of this expansion of DCCs takes place within 10 days following influenza infection. Strikingly, by 15 days post-infection, the lesions that expanded from solitary HER2+ DCCs almost homogeneously return to a quiescent state. Furthermore, we show interleukin-6 is required for the early phase of dormant cancer cells reawakening and proliferation and that CD4+ T cells are required for the maintenance of the expanded cancer cells post-infection at the late phase. Depletion of CD4 T cells (but not CD8 cells) during infection with influenza virus leads to the elimination of the expanded DCC population in the lung. Finally, single-cell RNA-seq analyses of DCC and microenvironmental cells in the lungs before and after infection reveals insight into underlying mechanisms for virus-induced awakening and reentry into dormancy. scRNA-seq analyses reveal that expanding DCC post-influenza infection reprogram CD4 and CD8 T-cells to a more immune suppressed state. These results support a model whereby pulmonary viral infections can increase the risk of metastatic relapse in the lungs for patients with a prior history of breast cancer. Thus, the immune response evolved to combat respiratory infections can be coopted and reprogrammed by dormant cancer cells to enable their expansion, thus increasing the odds of further metastatic cancer evolution. Ongoing work is currently being done to investigate this process in mouse models of SARS-CoV2 infection, as well as to examine clinical databases for epidemiological associations between respiratory viral infections and metastatic disease in the lung.
Citation Format: Bryan J. Johnson, Shi Biao Chia, Vadym Zaberezhnyy, Varsha Sreekanth, Meher Boorgula, Michael Papanicolaou, James Costello, Andrew Goodspeed, Julio A. Aguirre-Ghiso, Mercedes Rincon, James V. DeGregori. Influenza-induced inflammatory response reactivates and promotes dormant breast cancer cell outgrowth in lungs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B021.