TY - JOUR
T1 - BRAF inhibition alleviates immune suppression in murine autochthonous melanoma
AU - Steinberg, Shannon M.
AU - Zhang, Peisheng
AU - Malik, Brian T.
AU - Boni, Andrea
AU - Shabaneh, Tamer B.
AU - Byrne, Katelyn T.
AU - Mullins, David W.
AU - Brinckerhoff, Constance E.
AU - Ernstoff, Marc S.
AU - Bosenberg, Marcus W.
AU - Turk, Mary J.o.
N1 - Publisher Copyright:
©2014 American Association for Cancer Research.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - A growing body of evidence suggests that BRAF inhibitors, in addition to their acute tumor growth-inhibitory effects, can also promote immune responses to melanoma. The present study aimed to define the immunologic basis of BRAF-inhibitor therapy using the Braf/Pten model of inducible, autochthonous melanoma on a pure C57BL/6 background. In the tumor microenvironment, BRAF inhibitor PLX4720 functioned by on-target mechanisms to selectively decrease both the proportions and absolute numbers of CD4(+)Foxp3(+) regulatory T cells (Treg) and CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSC), while preserving numbers of CD8(+) effector T cells. In PLX4720-treated mice, the intratumoral Treg populations decreased significantly, demonstrating enhanced apopotosis. CD11b(+) myeloid cells from PLX4720-treated tumors also exhibited decreased immunosuppressive function on a per-cell basis. In accordance with a reversion of tumor immune suppression, tumors that had been treated with PLX4720 grew with reduced kinetics after treatment was discontinued, and this growth delay was dependent on CD8 T cells. These findings demonstrate that BRAF inhibition selectively reverses two major mechanisms of immunosuppression in melanoma and liberates host-adaptive antitumor immunity.
AB - A growing body of evidence suggests that BRAF inhibitors, in addition to their acute tumor growth-inhibitory effects, can also promote immune responses to melanoma. The present study aimed to define the immunologic basis of BRAF-inhibitor therapy using the Braf/Pten model of inducible, autochthonous melanoma on a pure C57BL/6 background. In the tumor microenvironment, BRAF inhibitor PLX4720 functioned by on-target mechanisms to selectively decrease both the proportions and absolute numbers of CD4(+)Foxp3(+) regulatory T cells (Treg) and CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSC), while preserving numbers of CD8(+) effector T cells. In PLX4720-treated mice, the intratumoral Treg populations decreased significantly, demonstrating enhanced apopotosis. CD11b(+) myeloid cells from PLX4720-treated tumors also exhibited decreased immunosuppressive function on a per-cell basis. In accordance with a reversion of tumor immune suppression, tumors that had been treated with PLX4720 grew with reduced kinetics after treatment was discontinued, and this growth delay was dependent on CD8 T cells. These findings demonstrate that BRAF inhibition selectively reverses two major mechanisms of immunosuppression in melanoma and liberates host-adaptive antitumor immunity.
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U2 - 10.1158/2326-6066.CIR-14-0074
DO - 10.1158/2326-6066.CIR-14-0074
M3 - Article
C2 - 25183499
AN - SCOPUS:84991510642
SN - 2326-6066
VL - 2
SP - 1044
EP - 1050
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 11
ER -