Use of non-small cell lung cancer multicellular tumor spheroids to study the impact of chemotherapy

• Published in: Respiratory research 2024-04, Vol.25 (1), p.156-156, Article 156
• Main Authors: Hulo, Pauline, Deshayes, Sophie, Fresquet, Judith, Chéné, Anne-Laure, Blandin, Stéphanie, Boisgerault, Nicolas, Fonteneau, Jean-François, Treps, Lucas, Denis, Marc G, Bennouna, Jaafar, Fradin, Delphine, Pons-Tostivint, Elvire, Blanquart, Christophe
• Format: Article
• Language: English
• Subjects: Cancer; Cancer cells; Cancer therapies; Carboplatin; Care and treatment; Cell culture; Cell cycle; Cell viability; Chemotherapies; Chemotherapy; Co-culture and PD-L1; Confocal microscopy; Diagnosis; DNA; DNA damage; DNA repair; Dosage and administration; Fibroblasts; Flow cytometry; Gemcitabine; Gene expression; Gene sequencing; Immunogenicity; Immunotherapy; Life Sciences; Lung cancer; Lung cancer, Non-small cell; Lung diseases; Lungs; Macrophages; Microscopy; Monocytes; Multicellular tumor spheroids; Neoplasms; Non-small cell lung carcinoma; Nucleotide sequence; Paclitaxel; Patient outcomes; PCR; PD-L1 protein; Resistance mechanisms; RNA sequencing; Small cell lung carcinoma; Spheroids; Survival; Testing; Transcriptomics; Tumor cell lines; Tumor cells; Tumors
• ISSN: 1465-993X; 1465-9921; 1465-993X; 1465-9921
• DOI: 10.1186/s12931-024-02791-5

Lung cancers represent the main cause of cancer related-death worldwide. Recently, immunotherapy alone or in combination with chemotherapy has deeply impacted the therapeutic care leading to an improved overall survival. However, relapse will finally occur, with no efficient second line treatment so far. New therapies development based on the comprehension of resistance mechanisms is necessary. However, the difficulties to obtain tumor samples before and after first line treatment hamper to clearly understand the consequence of these molecules on tumor cells and also to identify adapted second line therapies. To overcome this difficulty, we developed multicellular tumor spheroids (MCTS) using characterized Non-Small Cell Lung Cancer (NSCLC) cell lines, monocytes from healthy donors and fibroblasts. MCTS were treated with carboplatin-paclitaxel or -gemcitabine combinations according to clinical administration schedules. The treatments impact was studied using cell viability assay, histological analyses, 3'RNA sequencing, real-time PCR, flow cytometry and confocal microscopy. We showed that treatments induced a decrease in cell viability and strong modifications in the transcriptomic profile notably at the level of pathways involved in DNA damage repair and cell cycle. Interestingly, we also observed a modification of genes expression considered as hallmarks of response to immune check point inhibitors and immunogenicity, particularly an increase in CD274 gene expression, coding for PD-L1. This result was validated at the protein level and shown to be restricted to tumor cells on MCTS containing fibroblasts and macrophages. This increase was also observed in an additional cell line, expressing low basal CD274 level. This study shows that MCTS are interesting models to study the impact of first line therapies using conditions close to clinical practice and also to identify more adapted second line or concomitant therapies for lung cancer treatment.