Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth

被引：587

作者：

Kleffel, Sonja ^{[1
]}

Posch, Christian ^{[1
,2
]}

Barthel, Steven R. ^{[1
]}

Mueller, Hansgeorg ^{[1
,3
]}

Schlapbach, Christoph ^{[4
]}

Guenova, Emmanuella ^{[5
]}

Elco, Christopher P. ^{[1
,6
]}

Lee, Nayoung ^{[1
]}

Juneja, Vikram R. ^{[7
]}

Zhan, Qian ^{[6
]}

Lian, Christine G. ^{[6
]}

Thomi, Rahel ^{[4
]}

Hoetzenecker, Wolfram ^{[5
]}

Cozzio, Antonio ^{[5
]}

Dummer, Reinhard ^{[5
]}

Mihm, Martin C., Jr. ^{[1
]}

Flaherty, Keith T. ^{[8
]}

Frank, Markus H. ^{[1
,9
,10
]}

Murphy, George F. ^{[6
]}

Sharpe, Arlene H. ^{[6
,7
,11
]}

Kupper, Thomas S. ^{[1
]}

Schatton, Tobias ^{[1
,9
]}

机构：

[1] Harvard Univ, Sch Med, Dept Dermatol, Harvard Skin Dis Res Ctr,Brigham & Womens Hosp, Boston, MA 02115 USA

[2] Rudolfstiftung Hosp, Dept Dermatol, A-1030 Vienna, Austria

[3] Med Univ Innsbruck, Dept Dermatol, A-6020 Innsbruck, Austria

[4] Univ Bern, Dept Dermatol, CH-3010 Bern, Switzerland

[5] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland

[6] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Div Med Oncol, Massachusetts Gen Hosp,Canc Ctr, Boston, MA 02114 USA

[9] Harvard Univ, Sch Med, Dept Med, Childrens Hosp Boston, Boston, MA 02115 USA

[10] Edith Cowan Univ, Sch Med Sci, Joondalup, WA 6027, Australia

[11] Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Brigham & Womens Hosp, Boston, MA 02115 USA

来源：

CELL | 2015年 / 162卷 / 06期

基金：

瑞士国家科学基金会;

关键词：

BLOCKADE; ACTIVATION; EXPRESSION; NIVOLUMAB; RESPONSES; ANTI-PD-1; PATHWAYS; ANTIBODY; SAFETY; TIM-3;

D O I：

10.1016/j.cell.2015.08.052

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, themelanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.

引用

页码：1242 / 1256

页数：15

共 29 条

[11] The Activation of MAPK in Melanoma Cells Resistant to BRAF Inhibition Promotes PD-L1 Expression That Is Reversible by MEK and PI3K Inhibition [J].