KEY TAKEAWAYS
- The study aimed to investigate the impact of immunotherapy and chemo combinations on resistance mechanisms in lung cancer, addressing the need for effective 2L therapies.
- Researchers noticed the utility of MCTS as valuable models for assessing 1L therapies and identifying tailored 2L or concurrent treatments for lung cancer management.
Lung cancer, particularly non-small cell lung cancer (NSCLC), represents the leading cause of cancer-related mortality worldwide. The emergence of immunotherapy, either as a standalone treatment or in conjunction with chemotherapy (chemo), has notably transformed clinical management, culminating in enhanced overall survival (OS) rates. Despite these advancements, the inevitability of relapse underscores the imperative for efficacious second-line (2L) interventions, which are currently lacking.
The development of novel therapies hinges upon a comprehensive understanding of resistance mechanisms. However, the acquisition of tumor samples before and after first-line (1L) treatments poses a significant challenge, hindering the elucidation of the precise impact of these therapeutic agents on tumor cells and impeding the identification of tailored 2L therapies.
Pauline Hulo and the team aimed to assess the efficacy of 1L therapies using multicellular tumor spheroids (MCTS), thus shedding light on potential avenues for optimizing lung cancer treatment strategies.
They performed an inclusive analysis to overcome this difficulty, developing MCTS utilizing characterized NSCLC cell lines, monocytes from healthy donors, and fibroblasts. MCTS were subjected to treatment with carboplatin-paclitaxel or -gemcitabine combinations following clinical administration schedules. The impact of these treatments was assessed through cell viability assays, histological analyses, 3’RNA sequencing, real-time PCR, flow cytometry, and confocal microscopy.
The treatments induced a decrease in cell viability and significant modifications in the transcriptomic profile, particularly affecting pathways related to DNA damage repair and cell cycle regulation. Notably, alterations in gene expression associated with response to immune checkpoint inhibitors and immunogenicity were observed, including an increase in CD274 gene expression, encoding PD-L1. This elevation was confirmed at the protein level and observed predominantly in tumor cells within MCTS containing fibroblasts and macrophages. Additionally, this increase was consistent in another cell line with low basal CD274 expression.
The study concluded that MCTS serve as compelling models for investigating the effects of 1L therapies under conditions closely resembling clinical practice. Additionally, they offer a valuable platform for identifying more tailored 2L or concomitant therapies for the treatment of lung cancer.
The study was sponsored by the INSERM, CNRS, the Institut de Recherche en Santé Respiratoire des Pays de la Loire, Intergroupe Francophone de Cancérologie Thoracique (IFCT) and the Ligue contre le Cancer Grand-Ouest.
Source: https://pubmed.ncbi.nlm.nih.gov/38581044/
Hulo P, Deshayes S, Fresquet J, et al. (2024). “Use of non-small cell lung cancer multicellular tumor spheroids to study the impact of chemotherapy.” Respir Res. 2024 Apr 5;25(1):156. doi: 10.1186/s12931-024-02791-5. PMID: 38581044; PMCID: PMC10998296.
