Aspiration-induced orthotopic lung cancer model: a non-invasive method for in vivo tumor microenvironment studies

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Background Solid tumors account for the majority of cancer-associated morbidity, and the tumor microenvironment (TME) is a critical determinant of therapeutic response. However, the limited availability of optimized preclinical orthotopic cancer models that allow investigation of the TME constrains the development and evaluation of novel treatment approaches. Methods Here, we establish a non-invasive orthotopic lung cancer (OLC) model based on aspiration-mediated inoculation of luciferase-expressing Lewis lung carcinoma (LL2-luc2) cells, compared with the intranasal (i.n.) inoculation method. We monitored tumor progression weekly using in vivo bioluminescence imaging (BLI) and conducted welfare checks three times per week. We used endpoint histopathological analysis to validate tumor establishment and quantify tumor burden. Furthermore, we analyzed the tumor microenvironment (TME), to assess immune cell distribution and infiltration into the tumor. Results Inoculation of LL2-luc2 cells via aspiration resulted in consistent tumor engraftment across animals (6/6), with a defined humane endpoint between days 33–40 post-inoculation. Although the BLI signal enabled monitoring of established tumors, its quantitative correlation with histological tumor burden was limited. Analyzing lungs by immunofluorescence, we found that immune cells localized at the tumor borders, demonstrating a spatial distribution of CD3 + and MHCII + cells consistent with an immune-excluded-like microenvironment. Conclusions Together, our findings support the use of aspiration-based LL2-luc2 inoculation as a practical approach for studying tumor-microenvironment interactions.

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