Abstract 5844: Fibroblasts play an immunoregulatory role in lung cancer through exosome secretion and by controlling extracellular matrix composition

Introduction: Cancer associated fibroblasts (CAF) are increasingly recognized as central players in the regulation of the tumor immune microenvironment. In lung cancer however little is known about specific fibroblast subpopulations or mechanisms subtending their immunoregulatory potential. We previously identified the nuclear transporter XPO1 as a master controller of lung fibroblast protumorigenic potential. Here we evaluated the potential of fibroblasts to modulate interactions between immune and cancer cells. Material and Methods: Cultures of primary lung fibroblasts isolated from tissues resected during lung cancer surgery were characterized by multiparametric flow-cytometry and used for experiments with lung cancer cells and monocytes. Co-cultures, conditioned media and decellularized extracellular matrices deposited by fibroblasts (dECM) were employed to investigate different modes of interactions. Modulation of stemness and EMT properties were evaluated by flow cytometry and Real-Time PCR. Co-injection of dECM and lung cancer cell lines were performed in immunocompromised mice and heterotypic tumors were evaluated for their growth, local microenvironments and disseminating potential. Results and Discussions: Using fibroblast cultures form both cancer and normal lung tissue we detected protumorigenic potential also in cultures form normal lungs, in line with presence of classical activation markers (alpha-SMA, FAP). Bioactivity of fibroblasts include the ability to induce EMT and modulate stemness potential (increase of CD133+ cancer stem cells and CD133+/CXCR4+ metastasis initiating cells). Interestingly dECM displayed similar potential compared to co-cultures. Exosomes isolated from both CAF and normal fibroblasts also showed potential to induce conversion of normal monocytes into myeloid derived suppressor cells. In co-injection experiments, dECM from pro-tumorigenic fibroblasts regulated the local immune microenvironment of ensuing tumors inducing generation of a stroma with high content of COL1A and COL6A3, reducing the infiltration from NK cells and increasing neutrophil content, thereby favoring dissemination of cancer cells to distant organs. Pharmacological inhibition of fibroblast activation through compounds targeting XPO1 activity was able to reduce these effects and counteract fibroblast protumorigenic action. Conclusion: Fibroblasts play a regulatory role in tumor stroma and dissection of their activities could pave the way for rationale development of treatments to reverse immunosuppressive microenvironments. Citation Format: Giulia Bertolini, Elvira Pantano, Giuliana Pollaci, Federica Facchinetti, Ugo Pastorino, Gabriella Sozzi, Luca Roz. Fibroblasts play an immunoregulatory role in lung cancer through exosome secretion and by controlling extracellular matrix composition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5844.