Mesenchymal stem cell suppresses the efficacy of CAR-T toward killing lymphoma cells by modulating the microenvironment through stanniocalcin-1

Stem cells play critical roles both in the development of cancer and therapy resistance. Although mesenchymal stem cells (MSCs) can actively migrate to tumor sites, their impact on CAR-T immunotherapy has been little addressed. Using an in vitro cell co-culture model including lymphoma cells and macrophages, here we report that the CAR-T cell mediated cytotoxicity was significantly inhibited in the presence of MSCs. MSC caused an increase of CD4+ T cells and Treg cells but decrease of CD8+ T cells. In addition, MSCs stimulated the expression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death-ligand 1 (PD-L1) that contribute to the immune-suppressive function of tumor. Moreover, MSCs suppressed key components of NLRP3 inflammasome by modulating mitochondrial ROS release. Interestingly, all these suppressive events hindering CAR-T efficacy could be abrogated if the STC1 gene, which encodes the glycoprotein hormone staniocalcin-1, was knockdown in MSC. Using xenograft mice, we confirmed that CAR-T function could also be inhibited by MSC in vivo and STC1 played a critical role. These data revealed a novel function of MSC and staniocalcin-1 in suppressing CAR-T efficacy, which should be considered in cancer therapy and may also have potential applications in controlling the toxicity arising from excessive immune response.