Aging is a major risk factor in increased lung cancer incidence. While most research has focused on age-associated mutation accumulation to explain the late-life increase in cancer incidence, there are tissue environmental forces that both impede and promote cancer evolution. Just as organismal evolution is known to be driven by environmental changes, cellular (somatic) evolution in our bodies is similarly driven by changes in tissue environments. Environmental change promotes selection for new phenotypes that are adaptive to the new context. In our tissues, aging or insult-driven alterations in tissues drives selection for adaptive mutations, and some of these mutations can confer malignant phenotypes. Chronic, low-level inflammation has been associated with aging, termed inflammaging, yet how age-associated changes in lung tissue microenvironments contribute to increased lung cancer incidence has remained largely unknown. Since chronic inflammation has been shown to contribute to tumor development, we hypothesized that inflammaging contributes to increased oncogenic adaptation in the lung. Using either viral delivery of CRISPR constructs to mediate EML4-ALK translocations or ectopic expression of KRAS-G12D, we showed increased adenoma formation in old mice. Importantly, in the EML4-ALK model, we showed that the overexpression of alpha-1 antitrypsin (AAT) in old mice resulted in lower adenoma counts compared to their old wild type counterparts. Flow cytometric analysis of immune cells isolated from bronchoalveolar fluid of young and old mice showed an altered immune landscape, such as increased neutrophils, gamma delta T cells, and Foxp3+ regulatory T cells. Furthermore, analysis of the single-cell RNAseq data from Tabula Muris Consortium demonstrated increased exhaustion markers in the CD8+ T cells and regulatory T cells. Separately, Gene Set Enrichment Analysis (GSEA) of the differential gene expressions of lung epithelial cells isolated from young and old mice revealed enriched pathways related to immune activation and inflammatory response, and immune-suppression markers. Lastly, bulk RNA-seq from lungs of young, old, and old mice overexpressing AAT revealed increased immune cell exhaustion markers and that the overexpression of AAT partially reversed this increase. Finally, analysis of Genotype-Tissue Expression (GTEx) data comparing gene expressions in lungs of young and old humans similarly showed enriched pathways related to immune activation and increased T cell exhaustion markers in the elderly. In addition, using deconvolution methods CiberSort and xCell, we demonstrated altered innate and adaptive immune cell populations, for example, increased neutrophils and regulatory T cells, that are associated with advanced age, similar to aging mice. In conclusion, we showed that there is an exhausted immune microenvironment in aging lungs, that inflammation contributes to the increased tumor initiation, and that decreasing inflammation could decrease the lung tumor incidence by reactivating the immune system. Citation Format: Shi Biao Chia, Catherine Pham-Danis, Hannah Scarborough, Nathaniel Little, Etienne P. Danis, Andrew E. Goodspeed, Charles Dinarello, James DeGregori. Altered immune landscape in aging lungs contributes to malignant evolution [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A026.
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. The latest pandemic caused by the respiratory virus, SARS-CoV-2, has infected more than 600 million worldwide, with documented COVID-related death upward of 1 million in the United States alone. Respiratory viral infections result in increased inflammation with immune cell influx and expansion to facilitate viral clearance. Prior studies have shown that inflammation, including through neutrophils, can contribute to dormant cancer cells reawakening and outgrowth. Moreover, inhibition of IL6 has been shown to decrease breast cancer lung metastasis in mouse models. However, how respiratory viral infections contribute to breast cancer lung metastasis remains to be unraveled. Using MMTV/PyMT and MMTV/NEU mouse models of breast cancer lung metastasis and influenza A virus as a model respiratory virus, we demonstrated that acute influenza infection and the accompanying inflammation and immune cell influx awakens and dramatically increased proliferation and expansion of dormant disseminated cancer cells (DCC) in the lungs. Acute influenza infection leads to immune influx and expansion, including neutrophils and macrophages, with increased proportion of MHCII+ macrophages in early time points, and a sustained decrease in CD206+ macrophages starting 6 days post-infection until 28 days after the initial infection. Additionally, we observed a sustained accumulation of CD4+ T cells around expanding tumor cells for as long as 28 days after the infection. Notably, neutrophil depletion or IL6 knockout reversed the flu-induced dormant cell expansion in the lung. Finally, awakened DCC exhibited downregulation of vimentin immunoreactivity, suggesting a role for phenotypic plasticity in DCC outgrowth following viral infection. In conclusion, we show that respiratory viral infections awaken and increase proliferation of dormant breast cancer cells in the lung, and that depletion of neutrophils or blocking IL6 reverses influenza-induced dormant cell awakening and proliferation. Citation Format: Shi Biao Chia, Bryan Johnson, Julio A. Aguirre-Ghiso, Mercedes Rincon, James DeGregori. Pulmonary influenza infection promotes the awakening of dormant metastatic breast cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5131.
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