Project 2: Susceptibility of Lung Cancer Cells to SARS- CoV-2 Infection and Antibody-Mediated Neutralization

PROJECT 2: ABSTRACT Project 2 is based on evidence that lung cancer patients have higher susceptibility to SARS-CoV-2 infection and increased risk of severe disease and mortality. This increased vulnerability is likely due to a combination of factors, including immune-suppressing effects of the cancer itself or its treatment, age, pre-existing comorbidities, or smoking. Moreover, the potential elevated levels of the receptor for SARS-CoV-2, ACE2 protein, in tumor and tumor-adjacent normal tissues observed in cancer patients and in lungs of tobacco smoking individuals likely contributes to the susceptibility of these patients to SARS-CoV-2. Tumor cells are also known to be more permissive to viral replication due to defects in innate antiviral immunity. The potential for increased SARS-CoV-2 amplification in lung cancer cells might be a major factor contributing to enhanced COVID-19 disease in lung cancer patients. An increased susceptibility to viral infection and replication in lung cells in these patients might also impact the ability of neutralizing antibodies to block viral replication, making lung cancer patients more susceptible to SARS-CoV-2 infection and less able to become immune. Thus, a better understanding of the factors that impact SARS-CoV-2 replication in lung cancer and normal lung cells is needed for devising strategies to reduce the risk of lung cancer patients for severe COVID-19 disease, and for evaluation of the protective efficacy of future SARS-CoV-2 vaccines in these patients. To address these knowledge gaps, in Aim 1 we will identify factors associated with the inter-individual variation in susceptibility to infection by SARS- CoV-2 using an existing unique panel of human lung derived cancer and normal epithelial cells, and relate these factors to key clinical, demographic, and molecular features. We will use a combination of virological and genomics approaches, transcriptomics, and scRNAseq assays. The specificity of the susceptibility to SARS- CoV-2 infection will be evaluated by comparison to other respiratory viruses, such as influenza viruses. In Aim 2, we will characterize the functional activity of antibodies and antivirals in susceptible lung cancer and normal lung epithelial cells. Together with Project 1, we will determine the neutralizing potency of various antisera in susceptible lung cancer cells versus non-cancer respiratory tissue, and antibody dependent cellular cytotoxicity activities of antibodies in lung cancer versus normal lung epithelial cells. Lastly, we will determine the preclinical activity of drugs under clinical trial consideration in lung cancer cells vs. non-cancer respiratory tissue. Successful completion of these aims depend on our multi-disciplinary team, the clinical cohorts, biospecimens and resources provided by the Clinical and Data Sciences Cores and coordinated with overall U54 activities by the Administrative Core. In sum, these studies will provide new information on the determinants of the susceptibility of lung cancer patients to SARS-CoV-2 infection and uncover potential new therapeutic strategies.