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Verfasst von:Schatton, Tobias Franz Ioannis [VerfasserIn]   i
 Itoh, Yuta [VerfasserIn]   i
 Martins, Christina [VerfasserIn]   i
 Rasbach, Erik [VerfasserIn]   i
 Singh, Praveen [VerfasserIn]   i
 Silva, Mariana [VerfasserIn]   i
 Mucciarone, Kyla [VerfasserIn]   i
 Heppt, Markus V. [VerfasserIn]   i
 Geddes-Sweeney, Jenna [VerfasserIn]   i
 Stewart, Kate [VerfasserIn]   i
 Brandenburg, Anne [VerfasserIn]   i
 Liang, Jennifer [VerfasserIn]   i
 Dimitroff, Charles J. [VerfasserIn]   i
 Mihm, Martin C., Jr [VerfasserIn]   i
 Landsberg, Jennifer [VerfasserIn]   i
 Schlapbach, Christoph [VerfasserIn]   i
 Lian, Christine G. [VerfasserIn]   i
 Murphy, George F. [VerfasserIn]   i
 Kupper, Thomas S. [VerfasserIn]   i
 Ramsey, Matthew R. [VerfasserIn]   i
 Barthel, Steven R. [VerfasserIn]   i
Titel:Inhibition of melanoma cell-intrinsic Tim-3 stimulates MAPK-dependent tumorigenesis
Titelzusatz:tumor biology and immunology
Verf.angabe:Tobias Schatton, Yuta Itoh, Christina Martins, Erik Rasbach, Praveen Singh, Mariana Silva, Kyla Mucciarone, Markus V. Heppt, Jenna Geddes-Sweeney, Kate Stewart, Anne Brandenburg, Jennifer Liang, Charles J. Dimitroff, Martin C., Jr Mihm, Jennifer Landsberg, Christoph Schlapbach, Christine G. Lian, George F. Murphy, Thomas S. Kupper, Matthew R. Ramsey, and Steven R. Barthel
E-Jahr:2022
Jahr:August 18, 2022
Umfang:11 S.
Fussnoten:Gesehen am 22.08.2023
Titel Quelle:Enthalten in: Cancer research
Ort Quelle:Philadelphia, Pa. : AACR, 1916
Jahr Quelle:2022
Band/Heft Quelle:82(2022), 20 vom: Okt., Seite 3774-3784
ISSN Quelle:1538-7445
Abstract:T-cell immunoglobulin mucin family member 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because blockade of T-cell-Tim-3 enhances antitumor immunity. Here, we identify an additional role for Tim-3 as a growth-suppressive receptor intrinsic to melanoma cells. Inhibition of melanoma cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while melanoma-specific Tim-3 overexpression attenuated tumorigenesis. Ab-mediated Tim-3 blockade inhibited growth of immunogenic murine melanomas in T-cell-competent hosts, consistent with established antitumor effects of T-cell-Tim-3 inhibition. In contrast, Tim-3 Ab administration stimulated tumorigenesis of both highly and lesser immunogenic murine and human melanomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 activation suppressed, while its blockade enhanced, phosphorylation of pro-proliferative downstream MAPK signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and enhanced desired antitumor activity of Tim-3 interference in T-cell-competent hosts. These results identify melanoma-Tim-3 blockade as a mechanism that antagonizes T-cell-Tim-3-directed IO therapeutic efficacy. They further reveal MAPK targeting as a combination strategy for circumventing adverse consequences of unintended melanoma-Tim-3 inhibition.Tim-3 is a growth-suppressive receptor intrinsic to melanoma cells, the blockade of which promotes MAPK-dependent tumorigenesis and thus counteracts antitumor activity of T-cell-directed Tim-3 inhibition.
DOI:doi:10.1158/0008-5472.CAN-22-0970
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext: https://doi.org/10.1158/0008-5472.CAN-22-0970
 Volltext: https://aacrjournals.org/cancerres/article/82/20/3774/709635/Inhibition-of-Melanoma-Cell-Intrinsic-Tim-3
 DOI: https://doi.org/10.1158/0008-5472.CAN-22-0970
Datenträger:Online-Ressource
Sprache:eng
K10plus-PPN:1857205782
Verknüpfungen:→ Zeitschrift

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