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Research Article

Direct and Indirect Regulators of Epithelial-Mesenchymal Transition (EMT)-mediated Immunosuppression in Breast Carcinomas

Anushka Dongre, Mohammad Rashidian, Elinor Ng Eaton, Ferenc Reinhardt, Prathapan Thiru, Maria Zagorulya, Sunita Nepal, Tuba Banaz, Anna Martner, Stefani Spranger and Robert A. Weinberg
Anushka Dongre
1Whitehead Institute for Biomedical Research, Whitehead Institute for Biomedical Research
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Mohammad Rashidian
2Dana-Farber Cancer Institute
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Elinor Ng Eaton
3N/A, Whitehead Institute for Biomedical Research
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Ferenc Reinhardt
4Whitehead Institute for Biomedical Research
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Prathapan Thiru
3N/A, Whitehead Institute for Biomedical Research
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Maria Zagorulya
5Koch Institute for Integrative Cancer Research, MIT
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Sunita Nepal
3N/A, Whitehead Institute for Biomedical Research
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  • ORCID record for Sunita Nepal
Tuba Banaz
3N/A, Whitehead Institute for Biomedical Research
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  • ORCID record for Tuba Banaz
Anna Martner
6TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg
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Stefani Spranger
7Department of Biology, Massachusetts Institute of Technology
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Robert A. Weinberg
3N/A, Whitehead Institute for Biomedical Research
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  • For correspondence: weinberg@wi.mit.edu
DOI: 10.1158/2159-8290.CD-20-0603
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Abstract

The epithelial-to-mesenchymal transition (EMT), which conveys epithelial (E) carcinoma cells to quasi-mesenchymal (qM) states, enables them to metastasize and acquire resistance to certain treatments. Murine tumors composed of qM mammary carcinoma cells assemble an immunosuppressive tumor microenvironment (TME) and develop resistance to anti-CTLA4 immune checkpoint blockade therapy (ICB), unlike their E counterparts. Importantly, minority populations of qM cells within a tumor can cross-protect their more E neighbors from immune attack. The underlying mechanisms of immunosuppression and cross-protection have been unclear. We demonstrate that abrogation of qM carcinoma cell-derived factors (CD73, CSF1 or SPP1) prevents the assembly of an immunosuppressive TME and sensitizes otherwise refractory qM tumors partially or completely to anti-CTLA4 ICB. Most strikingly, mixed tumors in which minority populations of carcinoma cells no longer express CD73, are now sensitized to anti-CTLA4 ICB. Finally, loss of CD73 also enhances the efficacy of anti-CTLA4 ICB during the process of metastatic colonization.

  • Received May 5, 2020.
  • Revision received October 1, 2020.
  • Accepted December 11, 2020.
  • Copyright ©2020, American Association for Cancer Research.
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This OnlineFirst version was published on December 16, 2020
doi: 10.1158/2159-8290.CD-20-0603

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Direct and Indirect Regulators of Epithelial-Mesenchymal Transition (EMT)-mediated Immunosuppression in Breast Carcinomas
Anushka Dongre, Mohammad Rashidian, Elinor Ng Eaton, Ferenc Reinhardt, Prathapan Thiru, Maria Zagorulya, Sunita Nepal, Tuba Banaz, Anna Martner, Stefani Spranger and Robert A. Weinberg
Cancer Discov December 16 2020 DOI: 10.1158/2159-8290.CD-20-0603

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Direct and Indirect Regulators of Epithelial-Mesenchymal Transition (EMT)-mediated Immunosuppression in Breast Carcinomas
Anushka Dongre, Mohammad Rashidian, Elinor Ng Eaton, Ferenc Reinhardt, Prathapan Thiru, Maria Zagorulya, Sunita Nepal, Tuba Banaz, Anna Martner, Stefani Spranger and Robert A. Weinberg
Cancer Discov December 16 2020 DOI: 10.1158/2159-8290.CD-20-0603
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