In:
Science Advances, American Association for the Advancement of Science (AAAS), Vol. 7, No. 46 ( 2021-11-12)
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 + 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 Ccr2 hi F4/80 + 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.
Type of Medium:
Online Resource
ISSN:
2375-2548
DOI:
10.1126/sciadv.abi5790
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2021
detail.hit.zdb_id:
2810933-8
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