Immunomodulatory properties of cancer-associated fibroblasts in non-small cell lung cancer: studies in a 3D lung tumor model

Le résumé fourni par la source

Fibroblasts in the tumor microenvironment (TME), that are activated by tumor cells and thus reprogrammed into cancer-associated fibroblasts (CAFs), play an important role in the immune evasion of non-small cell lung cancer. The aim is to characterize the immunomodulatory expression profile during CAF formation under the influence of different lung cancer cell lines by establishing a 3D model consisting of CAFs. Healthy, human, bronchial fibroblasts isolated from thoracic operations were cultured on a biological collagen scaffold for 7 and 14 days. To generate CAFs, the 3D models were treated with conditioned media (cM) from HCC827 (with TGF-β) and Calu-3 lung cancer cell lines, respectively. CAF induction was verified by immunostaining for α-SMA, MCT4, FAP, and Caveolin-1 and by RT-qPCR for ACTA2. The expression of 7 factors involved in immune evasion (IL-6, CCL2, Chi3L1, TGF-β, CXCL12, IDO-1, VEGF) was analyzed by RT-qPCR and ELISA. In all 3D models with cM, there was a significant increase in α-SMA, FAP and ACTA2, indicating a successful CAF activation. Compared to control fibroblasts, CAFs in HCC827 cM showed a 2.17-fold and 3.6-fold higher expression of CCL2 and IL-6, respectively, whereas Chi3L1 was downregulated by almost 100%. Further, CAFs in Calu-3 cM showed a 1.9-fold increase in CCL2 expression, while 30% less CXCL12 was secreted compared to controls. The activation of fibroblasts into CAFs was successfully simulated in 3D models. The concomitant change in the immunomodulatory properties of CAFs can be induced in vitro by tumor cell lines and TGF- β. The established model can serve for future research on TME and the development of immunotherapies.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.