JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

Menée in vitro et in vivo, cette étude démontre que l'inhibition du système de transduction de signal JAK/STAT dans les macrophages favorise la résistance thérapeutique en induisant l'expression de facteurs protumorigènes

Résumé en anglais

Despite advances in treatment options, breast cancer remains the second leading cause of cancer-related death in women. Extensive efforts are underway to develop targeted therapies for specific subsets of breast cancer patients, including those with triple-negative breast cancer. Because the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is known to be oncogenic in tumor cells, inhibitors of this pathway are being extensively examined as candidates for targeted therapy in breast and other cancers. We demonstrate here that despite the antitumor effect of JAK/STAT inhibition on tumor cells, JAK/STAT inhibition acts on the tumor microenvironment to increase production of protumorigenic inflammatory factors, which promote therapeutic resistance. Furthermore, targeting inflammatory mediators improves responsiveness of tumors to JAK/STAT inhibition.Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in macrophages. We also demonstrate that loss of STAT3 in myeloid cells leads to enhanced mammary tumorigenesis. Further studies show that macrophages contribute to resistance of mammary tumors to the JAK/STAT inhibitor ruxolitinib in vivo and that ruxolitinib-treated macrophages produce soluble factors that promote resistance of tumor cells to JAK inhibition in vitro. Finally, we demonstrate that STAT3 deletion and JAK/STAT inhibition in macrophages increases expression of the protumorigenic factor cyclooxygenase-2 (COX-2), and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment.