Cancer-associated MSC drive tumor immune exclusion and resistance to immunotherapy, which can be overcome by Hedgehog inhibition

Sandra Cascio; Chelsea Chandler; Linan Zhang; Sarah Sinno; Bingsi Gao; Sayali Onkar; Tullia C Bruno; Dario A A Vignali; Haider Mahdi; Hatice U Osmanbeyoglu; Anda M Vlad; Lan G Coffman; Ronald J Buckanovich

doi:10.1126/sciadv.abi5790

Cancer-associated MSC drive tumor immune exclusion and resistance to immunotherapy, which can be overcome by Hedgehog inhibition

Sci Adv. 2021 Nov 12;7(46):eabi5790. doi: 10.1126/sciadv.abi5790. Epub 2021 Nov 12.

Authors

Sandra Cascio^{1

2}, Chelsea Chandler^{1

2}, Linan Zhang³, Sarah Sinno^{1

2}, Bingsi Gao^{1

2}, Sayali Onkar^{4

5}, Tullia C Bruno^{4

5

6}, Dario A A Vignali^{4

5

6}, Haider Mahdi^{1

2}, Hatice U Osmanbeyoglu^{3

7}, Anda M Vlad^{1

2}, Lan G Coffman^{1

2

8}, Ronald J Buckanovich^{1

2

8}

Affiliations

¹ Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
² Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
³ Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15213 USA.
⁴ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
⁵ Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.
⁶ Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.
⁷ Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.
⁸ Division of Hematology/Oncology, Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.

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^hiF4/80⁺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.

Abstract

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