Cancer-associated MSC drive tumor immune exclusion and resistance to immunotherapy, which can be overcome by Hedgehog inhibition
Menée notamment à l'aide d'un modèle murin de cancer de l'ovaire, cette étude met en évidence le rôle des cellules souches mésenchymateuses associées au cancer dans l'exclusion immunitaire et la résistance aux immunothérapies des cellules cancéreuses, puis démontre que l'inhibition de Hedgehog supprime les effets de ces cellules souches mésenchymateuses
We investigated the impact of cancer-associated mesenchymal stem cells (CA-MSCs) on ovarian tumor immunity. In patient samples, CA-MSC presence inversely correlates with the presence of intratumoral CD8+ T cells. Using an immune “hot” mouse ovarian cancer model, we found that CA-MSCs drive CD8+ T cell tumor immune exclusion and reduce response to anti–PD-L1 immune checkpoint inhibitor (ICI) via secretion of numerous chemokines (Ccl2, Cx3cl1, and Tgf-
β1), which recruit immune-suppressive CD14+Ly6C+Cx3cr1+ monocytic cells and polarize macrophages to an immune suppressive Ccr2hiF4/80+Cx3cr1+CD206+ phenotype. Both monocytes and macrophages express high levels of transforming growth factor β
–induced (Tgfbi) protein, which suppresses NK cell activity. Hedgehog inhibitor (HHi) therapy reversed CA-MSC effects, reducing myeloid cell presence and expression of Tgfbi, increasing intratumoral NK cell numbers, and restoring response to ICI therapy. Thus, CA-MSCs regulate antitumor immunity, and CA-MSC hedgehog signaling is an important target for cancer immunotherapy.
Science Advances , article en libre accès, 2020