The New York City area has become the hot spot of the COVID-19 pandemic in the United States with an estimated prevalence of >20%, based on preliminary serological tests. The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is increased among cancer patients, and their prognosis is worse. Patients with SARS-CoV-2 are more likely to have increased proinflammatory cytokines such as IFN-, IP-10, MCP-1, IL-1, IL-4 and IL-6, many of which have been associated with the pathogenesis of lung cancer and the development of immune checkpoint inhibitor (ICI) -related adverse events. However, the effects of prior SARS-CoV-2 infection on cancer pathogenesis and response to immunotherapy are not know. Under our parent R37 grant, we investigate the role of lower airway dysbiosis on the host immune tone, lung cancer pathogenesis, and the response to immunotherapy. Using and expanding the cohort ensembled under the parent R37 we will evaluate whether SARS-CoV-2 infection affects the lower airway immune tone promoting pro-tumor immunity and ICI-related pneumonitis. To test this, we will test whether prior SARS-CoV-2 infection is associated with protumor inflammation among patients with newly diagnosed NSCLC (New Aim 4) and whether SARS-CoV-2 predisposes patients to ICI-related pneumonitis (New Aim 5). To accomplished these aims we will use our expertise in the characterization of the lower airway microbiome (including the viral fraction) and the host immune profile. We will also take advantage of the high rate of COVID-19 seropositivity in the New York area and the collection of samples from our established bronchoscopy and thoracic surgery cohorts. In addition, we will use a novel RNA sequence approach that allows for the concomitant characterization of the RNA virome, the bacterial microbiome and he host transcriptome in the lower airways. Therefore, this is an unprecedented opportunity to conduct the necessary exploratory investigations on the effects of SARS-CoV-2 infection on the pathophysiology of cancer under the infrastructure established by the parent R37.