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

Dongre, Anushka (author)
Rashidian, Mohammad (author)
Eaton, Elinor Ng (author)
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Reinhardt, Ferenc (author)
Thiru, Prathapan (author)
Zagorulya, Maria (author)
Nepal, Sunita (author)
Banaz, Tuba (author)
Martner, Anna, 1979 (author)
Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för infektionssjukdomar,Sahlgrenska Centrum för Cancerforskning (SCCR),Institute of Biomedicine, Department of Infectious Medicine,Sahlgrenska Center for Cancer Research (SCCR)
Spranger, Stefani (author)
Weinberg, Robert A (author)
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 (creator_code:org_t)
2021
2021
English.
In: Cancer discovery. - 2159-8290. ; 11:5, s. 1286-1305
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

EMT; immunotherapy; CTLA-4; tumorimmunology; checkpoint blockade

Publication and Content Type

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