Abstract 1390: Pulmonary viral infection promotes the awakening of dormant metastatic breast cancer cells in lungs
Authors: Chia Shi Biao , Johnson Bryan , Boorgula Meher , Sreekanth Varsha , Goodspeed Andrew , Davenport Bennett J. , Hu Junxiao , Gao Dexiang , Papanicolaou Michael , Morrison Thomas E. , Aguirre-Ghiso Julio A. , Rincon Mercedes , DeGregori James V. 
Published: March 2024

Abstract
Background: 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. The most common sites of metastatic breast cancer are bone, liver, and lung. Respiratory viral infections inflict illnesses on countless people, as evidenced by annual flu seasons and the latest pandemic caused by SARS-CoV-2. Respiratory viral infections result in increased inflammation with immune cell influx to facilitate viral clearance. Prior studies have shown that inflammation can contribute to dormant cancer cells awakening and outgrowth. However, how respiratory viral infections contribute to breast cancer lung metastasis remains to be unraveled.
Methods: MMTV/NEU mouse model of dormant breast cancer was used, with influenza virus as the model respiratory virus. Lungs and bronchoalveolar lavage fluid were harvested for immunohistochemistry, flow cytometry, cytokines, and single-cell RNA-seq analysis. Flatiron Health Database was mined for epidemiological data to assess the risk of breast cancer metastasis to lung with COVID infection.
Results: We have shown a dramatic increase in disseminated cancer cell (DCC) awakening in the lungs following influenza and SARS-CoV-2 infections. Influenza infection results in loss of a pro-dormancy mesenchymal phenotype and increased proliferation of DCC in the lungs within days post-infection, with a more than 1000-fold expansion of carcinoma cells over a couple of weeks. Strikingly, by 15 days post-infection, the lesions that expanded from solitary HER2+ DCCs almost homogeneously return to a quiescent state. Our preliminary data indicate that post-infection increases in IL-6 are required for DCC expansion post-influenza. Acute influenza infection also contributed to an accumulation of CD4+ T cells around expanding tumor cells for as long as 28 days after the initial infection. Depletion of CD4+ T cells but not CD8+ cells during infection with influenza virus prevents the expansion of the DCCs in the lung. Co-depletion of CD8 cells with CD4 cells partially restored the DCC burden in the lungs, indicating a role for CD8 cells in eliminating DCCs when released from CD4-mediated suppression. Single-cell RNA-seq analyses of CD8+ T cells with CD4 depletion showed an increased IL2/STAT5, MTORC1, and Ox/Phos activation by 15 dpi. The analyses also showed an immunosuppressive effect by the tumor cells. Finally, analysis of female breast cancer patients who tested positive with SARS-CoV-2 after their initial diagnosis exhibited a hazard ratio of 1.44 (p=0.043) for subsequent diagnosis of metastatic breast cancer in lungs.
Conclusions: These studies reveal the potential risks to cancer survivors who experience respiratory viral infections, with mechanistic insight that could lead to novel prevention or intervention strategies.
Citation Format: Shi Biao Chia, Bryan Johnson, Meher Boorgula, Varsha Sreekanth, Andrew Goodspeed, Bennett J. Davenport, Junxiao Hu, Dexiang Gao, Michael Papanicolaou, Thomas E. Morrison, Julio A. Aguirre-Ghiso, Mercedes Rincon, James V. DeGregori. Pulmonary viral infection promotes the awakening of dormant metastatic breast cancer cells in lungs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1390.