Cancer-Associated Fibroblasts Serve as Decoys to Suppress NK Cell Anticancer Cytotoxicity in Breast Cancer

Aviad Ben-Shmuel; Yael Gruper; Coral Halperin; Oshrat Levi-Galibov; Hallel Rosenberg-Fogler; Debra Barki; Giulia Carradori; Yaniv Stein; Gal Yagel; Mariia Naumova; Shimrit Mayer; Maya Dadiani; Dana Morzaev-Sulzbach; Ofra Golani; Reinat Nevo; Ziv Porat; Einav Nili Gal-Yam; Ruth Scherz-Shouval

doi:10.1158/2159-8290.CD-24-0131

Cancer-Associated Fibroblasts Serve as Decoys to Suppress NK Cell Anticancer Cytotoxicity in Breast Cancer

Aviad Ben-Shmuel
, Yael Gruper
, Coral Halperin
, Oshrat Levi-Galibov
, Hallel Rosenberg-Fogler
, Debra Barki
, Giulia Carradori
, Yaniv Stein
, Gal Yagel
, Mariia Naumova
, Shimrit Mayer
, Maya Dadiani
, Dana Morzaev-Sulzbach
, Ofra Golani
, Reinat Nevo
, Ziv Porat
, Einav Nili Gal-Yam
, Ruth Scherz-Shouval^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

Cancer-associated fibroblasts (CAF) are abundant components of the breast tumor microenvironment and major contributors to immune-modulation. CAFs regulate the activity of many immune cells including T cells, macrophages, and dendritic cells; however, little is known about their interaction with NK cells, which constitute an important arm of antitumor immunity. Using mouse models of breast cancer and ex vivo cocultures, we find that CAFs inhibit NK cell cytotoxicity toward cancer cells. We unravel the mechanism by which suppression occurs, which is through ligand–receptor engagement between NK cells and CAFs, leading to CAF cytolysis and downregulation of activating receptor expression on NK cells, promoting cancer cell escape from NK cell surveillance. In patients with triple-negative breast cancer, we find enrichment of NK cells in CAF-rich regions and upregulation of NK-binding ligands on CAFs, which correlates with poor disease outcomes. These results reveal a CAF-mediated immunosuppressive decoy mechanism with implications for the treatment of carcinomas.

Original language	English
Pages (from-to)	1247-1269
Number of pages	23
Journal	Cancer Discovery
Volume	15
Issue number	6
DOIs	https://doi.org/10.1158/2159-8290.CD-24-0131
Publication status	Published - 1 Jun 2025

Funding

We would like to thank Dr. Liat Alyagor from the Department of Veterinary Resources at the Weizmann Institute of Science for her help optimizing the human TNBC TMAs MxIF staining. We thank the Scherz-Shouval lab members for helpful discussions. We thank Prof. Clare M Isackes from The Institute of Cancer Research, London, United Kingdom, for kindly sharing with us the D2A1 parental and D2A1 M2 mouse mammary cancer cell lines. A. Ben-Shmuel was funded through the Israeli Cancer Research Fund postdoctoral fellowship grant, 846856. R. Scherz-Shouval is incumbent of The Robert and Yadelle Sklare Professorial Chair in Biochemistry. This study was funded by European Research Council grant 101043300.

All Science Journal Classification (ASJC) codes

Oncology

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10.1158/2159-8290.CD-24-0131

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Ben-Shmuel, A., Gruper, Y., Halperin, C., Levi-Galibov, O., Rosenberg-Fogler, H., Barki, D., Carradori, G., Stein, Y., Yagel, G., Naumova, M., Mayer, S., Dadiani, M., Morzaev-Sulzbach, D., Golani, O., Nevo, R., Porat, Z., Nili Gal-Yam, E., & Scherz-Shouval, R. (2025). Cancer-Associated Fibroblasts Serve as Decoys to Suppress NK Cell Anticancer Cytotoxicity in Breast Cancer. Cancer Discovery, 15(6), 1247-1269. https://doi.org/10.1158/2159-8290.CD-24-0131

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title = "Cancer-Associated Fibroblasts Serve as Decoys to Suppress NK Cell Anticancer Cytotoxicity in Breast Cancer",

abstract = "Cancer-associated fibroblasts (CAF) are abundant components of the breast tumor microenvironment and major contributors to immune-modulation. CAFs regulate the activity of many immune cells including T cells, macrophages, and dendritic cells; however, little is known about their interaction with NK cells, which constitute an important arm of antitumor immunity. Using mouse models of breast cancer and ex vivo cocultures, we find that CAFs inhibit NK cell cytotoxicity toward cancer cells. We unravel the mechanism by which suppression occurs, which is through ligand–receptor engagement between NK cells and CAFs, leading to CAF cytolysis and downregulation of activating receptor expression on NK cells, promoting cancer cell escape from NK cell surveillance. In patients with triple-negative breast cancer, we find enrichment of NK cells in CAF-rich regions and upregulation of NK-binding ligands on CAFs, which correlates with poor disease outcomes. These results reveal a CAF-mediated immunosuppressive decoy mechanism with implications for the treatment of carcinomas.",

author = "Aviad Ben-Shmuel and Yael Gruper and Coral Halperin and Oshrat Levi-Galibov and Hallel Rosenberg-Fogler and Debra Barki and Giulia Carradori and Yaniv Stein and Gal Yagel and Mariia Naumova and Shimrit Mayer and Maya Dadiani and Dana Morzaev-Sulzbach and Ofra Golani and Reinat Nevo and Ziv Porat and \{Nili Gal-Yam\}, Einav and Ruth Scherz-Shouval",

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doi = "10.1158/2159-8290.CD-24-0131",

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Ben-Shmuel, A, Gruper, Y, Halperin, C, Levi-Galibov, O , Rosenberg-Fogler, H , Barki, D, Carradori, G, Stein, Y, Yagel, G, Naumova, M, Mayer, S, Dadiani, M, Morzaev-Sulzbach, D, Golani, O , Nevo, R , Porat, Z, Nili Gal-Yam, E & Scherz-Shouval, R 2025, 'Cancer-Associated Fibroblasts Serve as Decoys to Suppress NK Cell Anticancer Cytotoxicity in Breast Cancer', Cancer Discovery, vol. 15, no. 6, pp. 1247-1269. https://doi.org/10.1158/2159-8290.CD-24-0131

TY - JOUR

T1 - Cancer-Associated Fibroblasts Serve as Decoys to Suppress NK Cell Anticancer Cytotoxicity in Breast Cancer

AU - Ben-Shmuel, Aviad

AU - Gruper, Yael

AU - Halperin, Coral

AU - Levi-Galibov, Oshrat

AU - Rosenberg-Fogler, Hallel

AU - Barki, Debra

AU - Carradori, Giulia

AU - Stein, Yaniv

AU - Yagel, Gal

AU - Naumova, Mariia

AU - Mayer, Shimrit

AU - Dadiani, Maya

AU - Morzaev-Sulzbach, Dana

AU - Golani, Ofra

AU - Nevo, Reinat

AU - Porat, Ziv

AU - Nili Gal-Yam, Einav

AU - Scherz-Shouval, Ruth

PY - 2025/6/1

Y1 - 2025/6/1

N2 - Cancer-associated fibroblasts (CAF) are abundant components of the breast tumor microenvironment and major contributors to immune-modulation. CAFs regulate the activity of many immune cells including T cells, macrophages, and dendritic cells; however, little is known about their interaction with NK cells, which constitute an important arm of antitumor immunity. Using mouse models of breast cancer and ex vivo cocultures, we find that CAFs inhibit NK cell cytotoxicity toward cancer cells. We unravel the mechanism by which suppression occurs, which is through ligand–receptor engagement between NK cells and CAFs, leading to CAF cytolysis and downregulation of activating receptor expression on NK cells, promoting cancer cell escape from NK cell surveillance. In patients with triple-negative breast cancer, we find enrichment of NK cells in CAF-rich regions and upregulation of NK-binding ligands on CAFs, which correlates with poor disease outcomes. These results reveal a CAF-mediated immunosuppressive decoy mechanism with implications for the treatment of carcinomas.

AB - Cancer-associated fibroblasts (CAF) are abundant components of the breast tumor microenvironment and major contributors to immune-modulation. CAFs regulate the activity of many immune cells including T cells, macrophages, and dendritic cells; however, little is known about their interaction with NK cells, which constitute an important arm of antitumor immunity. Using mouse models of breast cancer and ex vivo cocultures, we find that CAFs inhibit NK cell cytotoxicity toward cancer cells. We unravel the mechanism by which suppression occurs, which is through ligand–receptor engagement between NK cells and CAFs, leading to CAF cytolysis and downregulation of activating receptor expression on NK cells, promoting cancer cell escape from NK cell surveillance. In patients with triple-negative breast cancer, we find enrichment of NK cells in CAF-rich regions and upregulation of NK-binding ligands on CAFs, which correlates with poor disease outcomes. These results reveal a CAF-mediated immunosuppressive decoy mechanism with implications for the treatment of carcinomas.

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SN - 2159-8274

VL - 15

SP - 1247

EP - 1269

JO - Cancer Discovery

JF - Cancer Discovery

IS - 6

ER -

Cancer-Associated Fibroblasts Serve as Decoys to Suppress NK Cell Anticancer Cytotoxicity in Breast Cancer

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