Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes

RAS‐MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKis) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cell...

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Autores principales:	Mikkel G. Terp, Odd L. Gammelgaard, Henriette Vever, Morten F. Gjerstorff, Henrik J. Ditzel
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	CD73 MAPKi p38‐MAPK RAS‐MAPK tumor microenvironment Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/f3d6962653184d478d74f58cf2f92dc3
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spelling	oai:doaj.org-article:f3d6962653184d478d74f58cf2f92dc32021-12-02T10:31:06ZSustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes1878-02611574-789110.1002/1878-0261.13046https://doaj.org/article/f3d6962653184d478d74f58cf2f92dc32021-12-01T00:00:00Zhttps://doi.org/10.1002/1878-0261.13046https://doaj.org/toc/1574-7891https://doaj.org/toc/1878-0261RAS‐MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKis) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cells remains incompletely understood. Here, we present evidence of a rapid compensatory response to MAPKi that is driven by sustained p38 MAPK signaling and by which cancer cells can upregulate the immunosuppressive protein CD73 to reduce the antitumor immune response. This compensatory response also results in decreased sensitivity toward MAPKi, and, accordingly, combining anti‐CD73 antibodies and MAPKi significantly enhances the antitumor effect compared to single‐agent treatment in vivo. Combining MAPKi and anti‐CD73 was accompanied by significant alterations in intratumor immune cell composition, supporting the effect of MAPKi‐induced CD73 expression on the TME. We show that high CD73 expression significantly correlates with worse outcome in MAPKi‐treated colorectal cancer patients, highlighting the potential clinical importance of increased CD73 expression following MAPKi treatment. Our findings may explain the diminished effect of MAPKi in cancer patients and provides further rationale for combined anti‐CD73 and MAPKi treatment.Mikkel G. TerpOdd L. GammelgaardHenriette VeverMorten F. GjerstorffHenrik J. DitzelWileyarticleCD73MAPKip38‐MAPKRAS‐MAPKtumor microenvironmentNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Oncology, Vol 15, Iss 12, Pp 3299-3316 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CD73 MAPKi p38‐MAPK RAS‐MAPK tumor microenvironment Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	CD73 MAPKi p38‐MAPK RAS‐MAPK tumor microenvironment Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Mikkel G. Terp Odd L. Gammelgaard Henriette Vever Morten F. Gjerstorff Henrik J. Ditzel Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes
description	RAS‐MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKis) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cells remains incompletely understood. Here, we present evidence of a rapid compensatory response to MAPKi that is driven by sustained p38 MAPK signaling and by which cancer cells can upregulate the immunosuppressive protein CD73 to reduce the antitumor immune response. This compensatory response also results in decreased sensitivity toward MAPKi, and, accordingly, combining anti‐CD73 antibodies and MAPKi significantly enhances the antitumor effect compared to single‐agent treatment in vivo. Combining MAPKi and anti‐CD73 was accompanied by significant alterations in intratumor immune cell composition, supporting the effect of MAPKi‐induced CD73 expression on the TME. We show that high CD73 expression significantly correlates with worse outcome in MAPKi‐treated colorectal cancer patients, highlighting the potential clinical importance of increased CD73 expression following MAPKi treatment. Our findings may explain the diminished effect of MAPKi in cancer patients and provides further rationale for combined anti‐CD73 and MAPKi treatment.
format	article
author	Mikkel G. Terp Odd L. Gammelgaard Henriette Vever Morten F. Gjerstorff Henrik J. Ditzel
author_facet	Mikkel G. Terp Odd L. Gammelgaard Henriette Vever Morten F. Gjerstorff Henrik J. Ditzel
author_sort	Mikkel G. Terp
title	Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes
title_short	Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes
title_full	Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes
title_fullStr	Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes
title_full_unstemmed	Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes
title_sort	sustained compensatory p38 mapk signaling following treatment with mapk inhibitors induces the immunosuppressive protein cd73 in cancer: combined targeting could improve outcomes
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/f3d6962653184d478d74f58cf2f92dc3
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Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes

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