Age-related features of cancer stem cell and T-cell response to therapy in a lung cancer model in aged mice

Metastasis and tumor recurrence are closely linked to highly resistant cancer stem cells (CSCs). It is unclear how the content of CSCs changes with age in cancer development and whether these changes correlate with a higher incidence of tumors in elderly individuals. Previously, we demonstrated the positive effect of reprogrammed CD8⁺ T-cells (rCD8-T) derived from the bone marrow of young mice with Lewis lung carcinomas (LLCs) on CSCs.

Lung cancer was modeled by injecting LLC cells into C57/BL6 mice (aged 80–82 weeks). On day 7, morphological and histological examinations of the lungs were conducted, along with cytometric analyses to quantify populations of CSCs, CD4, and CD8 T-cells in blood and lungs.

In aged mice receiving rCD8-T therapy, there was a significant reduction in lung tumor growth activity. However, notable histopathological changes were observed, characterized by extensive patchy necrosis within the livers of treated animals. Additionally, rCD8-T therapy led to a marked expansion of various CD4⁺ and CD8⁺ T-cell subsets in blood (up to 1,000-fold increases) and lung tissues (approximately 2-4-fold increases) compared to tumor-bearing mice without treatment. Notably, while untreated mice exhibited reduced numbers of circulating CD4⁺ and CD8⁺ T-cells, the population of CSCs expressing the Sox2 marker - associated with more aggressive tumor phenotypes increased substantially. After treatment, however, the frequency of Sox2-positive CSCs in circulation declined compared to those in untreated animals. In contrast, CSCs in the lungs showed little change.

Therefore, rCD8-T therapy in aged mice, although beneficial for reducing tumor growth and eliminating CSCs, induces hyperactivation of the immune system. To enhance therapeutic efficacy and ensure safety in elderly patients with lung cancer, targeted approaches against Sox2 expressing CSCs may prove effective. Combining these strategies with conventional chemotherapeutic regimens holds promise for improving overall survival outcomes in this patient population.