Cancer-associated MSC drive tumor immune exclusion and resistance to immunotherapy, which can be overcome by Hedgehog inhibition.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34767446.
- Also identified by DOI 10.1126/sciadv.abi5790 and PMC identifier 8589308.
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Abstract
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<sup>+</sup> T cells. Using an immune “hot” mouse ovarian cancer model, we found that CA-MSCs drive CD8<sup>+</sup> 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<sup>+</sup>Ly6C<sup>+</sup>Cx3cr1<sup>+</sup> monocytic cells and polarize macrophages to an immune suppressive Ccr2<sup>hi</sup>F4/80<sup>+</sup>Cx3cr1<sup>+</sup>CD206<sup>+</sup> 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.