CD95/Fas protects triple negative breast cancer from anti-tumor activity of NK cells

Abdul S. Qadir; Jean Philippe Guégan; Christophe Ginestier; Assia Chaibi; Alban Bessede; Emmanuelle Charafe-Jauffret; Manon Macario; Vincent Lavoué; Thibault de la Motte Rouge; Calvin Law; Jacob Vilker; Hongbin Wang; Emily Stroup; Matthew J. Schipma; Bryan Bridgeman; Andrea E. Murmann; Zhe Ji; Patrick Legembre; Marcus E. Peter

doi:10.1016/j.isci.2021.103348

CD95/Fas protects triple negative breast cancer from anti-tumor activity of NK cells

Abdul S. Qadir, Jean Philippe Guégan, Christophe Ginestier, Assia Chaibi, Alban Bessede, Emmanuelle Charafe-Jauffret, Manon Macario, Vincent Lavoué, Thibault de la Motte Rouge, Calvin Law, Jacob Vilker, Hongbin Wang, Emily Stroup, Matthew J. Schipma, Bryan Bridgeman, Andrea E. Murmann, Zhe Ji, Patrick Legembre^*, Marcus E. Peter^*

^*Corresponding author for this work

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

11 Scopus citations

Abstract

The apoptosis inducing receptor CD95/Fas has multiple tumorigenic activities. In different genetically engineered mouse models tumor-expressed CD95 was shown to be critical for cell growth. Using a combination of immune-deficient and immune-competent mouse models, we now establish that loss of CD95 in metastatic triple negative breast cancer (TNBC) cells prevents tumor growth by modulating the immune landscape. CD95-deficient, but not wild-type, tumors barely grow in an immune-competent environment and show an increase in immune infiltrates into the tumor. This growth reduction is caused by infiltrating NK cells and does not involve T cells or macrophages. In contrast, in immune compromised mice CD95 k.o. cells are not growth inhibited, but they fail to form metastases. In summary, we demonstrate that in addition to its tumor and metastasis promoting activities, CD95 expression by tumor cells can exert immune suppressive activities on NK cells, providing a new target for immune therapy.

Original language	English (US)
Article number	103348
Journal	iScience
Volume	24
Issue number	11
DOIs	https://doi.org/10.1016/j.isci.2021.103348
State	Published - Nov 19 2021

Funding

U-clones: we would like to thank Shanshan Zhang for performing slide scanning and signal quantification, Michelle von Locquenghien for help with the generation of the 4T1 CD95 k.o. clones, and Bin Zhang for giving advice. F-clones: we would like to thank the IHC facility (Dr. Alain Fautrel and Roselyne Viel, Rennes, France) for performing 4T1 tissue staining, slide scanning, and signal quantification. The mouse study in NSG mice benefited from the help of Remy Castellano and Emmanuelle Josselin (Marseille, France). This work was funded by grant R35CA197450 to M.E.P, by INCa (PLBIO18-059), Ligue Contre le Cancer and Fondation de France (Price Jean Valade) for P.L. and by Lynn Sage Cancer Research Foundation and Lynn Sage Scholar fund for Z.J. ASQ, JPG, CG, EC-J, AB, VL, TMR, PL, ZJ, and MEP planned the experiments. ASQ, JPG, CL, HW, ES, AC, JV, MJS, MM, AEM, and BB performed experiments or analyzed data. PL and MEP directed the study and wrote the manuscript. The authors declare that they have no conflict of interest. U-clones: we would like to thank Shanshan Zhang for performing slide scanning and signal quantification, Michelle von Locquenghien for help with the generation of the 4T1 CD95 k.o. clones, and Bin Zhang for giving advice. F-clones: we would like to thank the IHC facility (Dr. Alain Fautrel and Roselyne Viel, Rennes, France) for performing 4T1 tissue staining, slide scanning, and signal quantification. The mouse study in NSG mice benefited from the help of Remy Castellano and Emmanuelle Josselin (Marseille, France). This work was funded by grant R35CA197450 to M.E.P, by INCa (PLBIO18-059), Ligue Contre le Cancer and Fondation de France (Price Jean Valade) for P.L., and by Lynn Sage Cancer Research Foundation and Lynn Sage Scholar fund for Z.J.

Keywords

Cancer
Cell biology
Immunology

ASJC Scopus subject areas

General

UN SDGs

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

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10.1016/j.isci.2021.103348

Cite this

Qadir, A. S., Guégan, J. P., Ginestier, C., Chaibi, A., Bessede, A., Charafe-Jauffret, E., Macario, M., Lavoué, V., Rouge, T. D. L. M., Law, C., Vilker, J., Wang, H., Stroup, E., Schipma, M. J., Bridgeman, B., Murmann, A. E., Ji, Z., Legembre, P., & Peter, M. E. (2021). CD95/Fas protects triple negative breast cancer from anti-tumor activity of NK cells. iScience, 24(11), Article 103348. https://doi.org/10.1016/j.isci.2021.103348

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title = "CD95/Fas protects triple negative breast cancer from anti-tumor activity of NK cells",

abstract = "The apoptosis inducing receptor CD95/Fas has multiple tumorigenic activities. In different genetically engineered mouse models tumor-expressed CD95 was shown to be critical for cell growth. Using a combination of immune-deficient and immune-competent mouse models, we now establish that loss of CD95 in metastatic triple negative breast cancer (TNBC) cells prevents tumor growth by modulating the immune landscape. CD95-deficient, but not wild-type, tumors barely grow in an immune-competent environment and show an increase in immune infiltrates into the tumor. This growth reduction is caused by infiltrating NK cells and does not involve T cells or macrophages. In contrast, in immune compromised mice CD95 k.o. cells are not growth inhibited, but they fail to form metastases. In summary, we demonstrate that in addition to its tumor and metastasis promoting activities, CD95 expression by tumor cells can exert immune suppressive activities on NK cells, providing a new target for immune therapy.",

keywords = "Cancer, Cell biology, Immunology",

author = "Qadir, {Abdul S.} and Gu{\'e}gan, {Jean Philippe} and Christophe Ginestier and Assia Chaibi and Alban Bessede and Emmanuelle Charafe-Jauffret and Manon Macario and Vincent Lavou{\'e} and Rouge, {Thibault de la Motte} and Calvin Law and Jacob Vilker and Hongbin Wang and Emily Stroup and Schipma, {Matthew J.} and Bryan Bridgeman and Murmann, {Andrea E.} and Zhe Ji and Patrick Legembre and Peter, {Marcus E.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = nov,

day = "19",

doi = "10.1016/j.isci.2021.103348",

language = "English (US)",

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Qadir, AS, Guégan, JP, Ginestier, C, Chaibi, A, Bessede, A, Charafe-Jauffret, E, Macario, M, Lavoué, V, Rouge, TDLM, Law, C, Vilker, J, Wang, H, Stroup, E, Schipma, MJ, Bridgeman, B, Murmann, AE , Ji, Z, Legembre, P & Peter, ME 2021, 'CD95/Fas protects triple negative breast cancer from anti-tumor activity of NK cells', iScience, vol. 24, no. 11, 103348. https://doi.org/10.1016/j.isci.2021.103348

TY - JOUR

T1 - CD95/Fas protects triple negative breast cancer from anti-tumor activity of NK cells

AU - Qadir, Abdul S.

AU - Guégan, Jean Philippe

AU - Ginestier, Christophe

AU - Chaibi, Assia

AU - Bessede, Alban

AU - Charafe-Jauffret, Emmanuelle

AU - Macario, Manon

AU - Lavoué, Vincent

AU - Rouge, Thibault de la Motte

AU - Law, Calvin

AU - Vilker, Jacob

AU - Wang, Hongbin

AU - Stroup, Emily

AU - Schipma, Matthew J.

AU - Bridgeman, Bryan

AU - Murmann, Andrea E.

AU - Ji, Zhe

AU - Legembre, Patrick

AU - Peter, Marcus E.

PY - 2021/11/19

Y1 - 2021/11/19

N2 - The apoptosis inducing receptor CD95/Fas has multiple tumorigenic activities. In different genetically engineered mouse models tumor-expressed CD95 was shown to be critical for cell growth. Using a combination of immune-deficient and immune-competent mouse models, we now establish that loss of CD95 in metastatic triple negative breast cancer (TNBC) cells prevents tumor growth by modulating the immune landscape. CD95-deficient, but not wild-type, tumors barely grow in an immune-competent environment and show an increase in immune infiltrates into the tumor. This growth reduction is caused by infiltrating NK cells and does not involve T cells or macrophages. In contrast, in immune compromised mice CD95 k.o. cells are not growth inhibited, but they fail to form metastases. In summary, we demonstrate that in addition to its tumor and metastasis promoting activities, CD95 expression by tumor cells can exert immune suppressive activities on NK cells, providing a new target for immune therapy.

AB - The apoptosis inducing receptor CD95/Fas has multiple tumorigenic activities. In different genetically engineered mouse models tumor-expressed CD95 was shown to be critical for cell growth. Using a combination of immune-deficient and immune-competent mouse models, we now establish that loss of CD95 in metastatic triple negative breast cancer (TNBC) cells prevents tumor growth by modulating the immune landscape. CD95-deficient, but not wild-type, tumors barely grow in an immune-competent environment and show an increase in immune infiltrates into the tumor. This growth reduction is caused by infiltrating NK cells and does not involve T cells or macrophages. In contrast, in immune compromised mice CD95 k.o. cells are not growth inhibited, but they fail to form metastases. In summary, we demonstrate that in addition to its tumor and metastasis promoting activities, CD95 expression by tumor cells can exert immune suppressive activities on NK cells, providing a new target for immune therapy.

KW - Cancer

KW - Cell biology

KW - Immunology

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AN - SCOPUS:85118852525

SN - 2589-0042

VL - 24

JO - iScience

JF - iScience

IS - 11

M1 - 103348

ER -

CD95/Fas protects triple negative breast cancer from anti-tumor activity of NK cells

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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