A SOX9-B7x axis safeguards dedifferentiated tumor cells from immune surveillance to drive breast cancer progression

Yu Liu; Peter John; Kenta Nishitani; Jihong Cui; Christopher D. Nishimura; John R. Christin; Nicole Couturier; Xiaoxin Ren; Yao Wei; Marc C. Pulanco; Phillip M. Galbo; Xusheng Zhang; Wenyan Fu; Wei Cui; Boris A. Bartholdy; Deyou Zheng; Gregoire Lauvau; Susan A. Fineberg; Maja H. Oktay; Xingxing Zang; Wenjun Guo

doi:10.1016/j.devcel.2023.10.010

A SOX9-B7x axis safeguards dedifferentiated tumor cells from immune surveillance to drive breast cancer progression

Yu Liu, Peter John, Kenta Nishitani, Jihong Cui, Christopher D. Nishimura, John R. Christin, Nicole Couturier, Xiaoxin Ren, Yao Wei, Marc C. Pulanco, Phillip M. Galbo, Xusheng Zhang, Wenyan Fu, Wei Cui, Boris A. Bartholdy, Deyou Zheng, Gregoire Lauvau, Susan A. Fineberg, Maja H. Oktay, Xingxing ZangWenjun Guo

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

Abstract

How dedifferentiated stem-like tumor cells evade immunosurveillance remains poorly understood. We show that the lineage-plasticity regulator SOX9, which is upregulated in dedifferentiated tumor cells, limits the number of infiltrating T lymphocytes in premalignant lesions of mouse basal-like breast cancer. SOX9-mediated immunosuppression is required for the progression of in situ tumors to invasive carcinoma. SOX9 induces the expression of immune checkpoint B7x/B7-H4 through STAT3 activation and direct transcriptional regulation. B7x is upregulated in dedifferentiated tumor cells and protects them from immunosurveillance. B7x also protects mammary gland regeneration in immunocompetent mice. In advanced tumors, B7x targeting inhibits tumor growth and overcomes resistance to anti-PD-L1 immunotherapy. In human breast cancer, SOX9 and B7x expression are correlated and associated with reduced CD8⁺ T cell infiltration. This study, using mouse models, cell lines, and patient samples, identifies a dedifferentiation-associated immunosuppression mechanism and demonstrates the therapeutic potential of targeting the SOX9-B7x pathway in basal-like breast cancer.

Original language	English (US)
Pages (from-to)	2700-2717.e12
Journal	Developmental cell
Volume	58
Issue number	23
DOIs	https://doi.org/10.1016/j.devcel.2023.10.010
State	Published - Dec 4 2023

Keywords

B7-H4
B7x
DCIS progression
Sox9
VTCN1
breast cancer
dedifferentiation
immune checkpoint
stem cells
tumor-infiltrating lymphocyte

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.devcel.2023.10.010

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Liu, Y., John, P., Nishitani, K., Cui, J., Nishimura, C. D., Christin, J. R., Couturier, N., Ren, X., Wei, Y., Pulanco, M. C., Galbo, P. M., Zhang, X., Fu, W., Cui, W., Bartholdy, B. A., Zheng, D., Lauvau, G., Fineberg, S. A., Oktay, M. H., ... Guo, W. (2023). A SOX9-B7x axis safeguards dedifferentiated tumor cells from immune surveillance to drive breast cancer progression. Developmental cell, 58(23), 2700-2717.e12. https://doi.org/10.1016/j.devcel.2023.10.010

Liu, Y, John, P, Nishitani, K, Cui, J, Nishimura, CD, Christin, JR, Couturier, N, Ren, X, Wei, Y, Pulanco, MC, Galbo, PM, Zhang, X, Fu, W, Cui, W, Bartholdy, BA, Zheng, D , Lauvau, G, Fineberg, SA, Oktay, MH , Zang, X & Guo, W 2023, 'A SOX9-B7x axis safeguards dedifferentiated tumor cells from immune surveillance to drive breast cancer progression', Developmental cell, vol. 58, no. 23, pp. 2700-2717.e12. https://doi.org/10.1016/j.devcel.2023.10.010

@article{658851ae91a349fb9b336d6b874afa18,

title = "A SOX9-B7x axis safeguards dedifferentiated tumor cells from immune surveillance to drive breast cancer progression",

abstract = "How dedifferentiated stem-like tumor cells evade immunosurveillance remains poorly understood. We show that the lineage-plasticity regulator SOX9, which is upregulated in dedifferentiated tumor cells, limits the number of infiltrating T lymphocytes in premalignant lesions of mouse basal-like breast cancer. SOX9-mediated immunosuppression is required for the progression of in situ tumors to invasive carcinoma. SOX9 induces the expression of immune checkpoint B7x/B7-H4 through STAT3 activation and direct transcriptional regulation. B7x is upregulated in dedifferentiated tumor cells and protects them from immunosurveillance. B7x also protects mammary gland regeneration in immunocompetent mice. In advanced tumors, B7x targeting inhibits tumor growth and overcomes resistance to anti-PD-L1 immunotherapy. In human breast cancer, SOX9 and B7x expression are correlated and associated with reduced CD8+ T cell infiltration. This study, using mouse models, cell lines, and patient samples, identifies a dedifferentiation-associated immunosuppression mechanism and demonstrates the therapeutic potential of targeting the SOX9-B7x pathway in basal-like breast cancer.",

keywords = "B7-H4, B7x, DCIS progression, Sox9, VTCN1, breast cancer, dedifferentiation, immune checkpoint, stem cells, tumor-infiltrating lymphocyte",

author = "Yu Liu and Peter John and Kenta Nishitani and Jihong Cui and Nishimura, {Christopher D.} and Christin, {John R.} and Nicole Couturier and Xiaoxin Ren and Yao Wei and Pulanco, {Marc C.} and Galbo, {Phillip M.} and Xusheng Zhang and Wenyan Fu and Wei Cui and Bartholdy, {Boris A.} and Deyou Zheng and Gregoire Lauvau and Fineberg, {Susan A.} and Oktay, {Maja H.} and Xingxing Zang and Wenjun Guo",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = dec,

day = "4",

doi = "10.1016/j.devcel.2023.10.010",

language = "English (US)",

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AU - Liu, Yu

AU - John, Peter

AU - Nishitani, Kenta

AU - Cui, Jihong

AU - Nishimura, Christopher D.

AU - Christin, John R.

AU - Couturier, Nicole

AU - Ren, Xiaoxin

AU - Wei, Yao

AU - Pulanco, Marc C.

AU - Galbo, Phillip M.

AU - Zhang, Xusheng

AU - Fu, Wenyan

AU - Cui, Wei

AU - Bartholdy, Boris A.

AU - Zheng, Deyou

AU - Lauvau, Gregoire

AU - Fineberg, Susan A.

AU - Oktay, Maja H.

AU - Zang, Xingxing

AU - Guo, Wenjun

PY - 2023/12/4

Y1 - 2023/12/4

N2 - How dedifferentiated stem-like tumor cells evade immunosurveillance remains poorly understood. We show that the lineage-plasticity regulator SOX9, which is upregulated in dedifferentiated tumor cells, limits the number of infiltrating T lymphocytes in premalignant lesions of mouse basal-like breast cancer. SOX9-mediated immunosuppression is required for the progression of in situ tumors to invasive carcinoma. SOX9 induces the expression of immune checkpoint B7x/B7-H4 through STAT3 activation and direct transcriptional regulation. B7x is upregulated in dedifferentiated tumor cells and protects them from immunosurveillance. B7x also protects mammary gland regeneration in immunocompetent mice. In advanced tumors, B7x targeting inhibits tumor growth and overcomes resistance to anti-PD-L1 immunotherapy. In human breast cancer, SOX9 and B7x expression are correlated and associated with reduced CD8+ T cell infiltration. This study, using mouse models, cell lines, and patient samples, identifies a dedifferentiation-associated immunosuppression mechanism and demonstrates the therapeutic potential of targeting the SOX9-B7x pathway in basal-like breast cancer.

AB - How dedifferentiated stem-like tumor cells evade immunosurveillance remains poorly understood. We show that the lineage-plasticity regulator SOX9, which is upregulated in dedifferentiated tumor cells, limits the number of infiltrating T lymphocytes in premalignant lesions of mouse basal-like breast cancer. SOX9-mediated immunosuppression is required for the progression of in situ tumors to invasive carcinoma. SOX9 induces the expression of immune checkpoint B7x/B7-H4 through STAT3 activation and direct transcriptional regulation. B7x is upregulated in dedifferentiated tumor cells and protects them from immunosurveillance. B7x also protects mammary gland regeneration in immunocompetent mice. In advanced tumors, B7x targeting inhibits tumor growth and overcomes resistance to anti-PD-L1 immunotherapy. In human breast cancer, SOX9 and B7x expression are correlated and associated with reduced CD8+ T cell infiltration. This study, using mouse models, cell lines, and patient samples, identifies a dedifferentiation-associated immunosuppression mechanism and demonstrates the therapeutic potential of targeting the SOX9-B7x pathway in basal-like breast cancer.

KW - B7-H4

KW - B7x

KW - DCIS progression

KW - Sox9

KW - VTCN1

KW - breast cancer

KW - dedifferentiation

KW - immune checkpoint

KW - stem cells

KW - tumor-infiltrating lymphocyte

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SN - 1534-5807

VL - 58

SP - 2700-2717.e12

JO - Developmental cell

JF - Developmental cell

IS - 23

ER -

A SOX9-B7x axis safeguards dedifferentiated tumor cells from immune surveillance to drive breast cancer progression

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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