Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling

被引：14

作者：

Martins, Christina ^{[1
,2
]}

Rasbach, Erik ^{[1
,2
,3
]}

Heppt, Markus V. ^{[1
,4
]}

Singh, Praveen ^{[1
,2
]}

Kulcsar, Zsofi ^{[1
,2
,5
]}

Holzgruber, Julia ^{[1
,2
,6
]}

Chakraborty, Asmi ^{[1
,2
]}

Mucciarone, Kyla ^{[7
]}

Kleffel, Sonja ^{[1
]}

Brandenburg, Anne ^{[1
,5
]}

Hoetzenecker, Wolfram ^{[6
]}

Rahbari, Nuh N. ^{[3
]}

Decaprio, James A. ^{[8
,9
,10
]}

Thakuria, Manisha ^{[1
,10
]}

Murphy, George F. ^{[7
]}

Ramsey, Matthew R. ^{[1
]}

Posch, Christian ^{[1
,11
,12
,13
]}

Barthel, Steven R. ^{[1
,2
]}

Schatton, Tobias ^{[1
,2
,14
]}

机构：

[1] Harvard Med Sch, Dept Dermatol, Brigham & Womens Hosp, Boston, MA 02115 USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Program Glyco Immunol & Oncol, Boston, MA 02115 USA

[3] Heidelberg Univ, Univ Hosp Mannheim, Dept Surg, D-68167 Mannheim, Germany

[4] Friedrich Alexander Univ FAU, Univ Hosp Erlangen, Dept Dermatol, D-91054 Erlangen, Germany

[5] Univ Hosp Bonn, Dept Dermatol, D-53127 Bonn, Germany

[6] Johannes Kepler Univ Linz, Dept Dermatol & Venerol, A-4020 Linz, Austria

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

[8] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[9] Harvard Univ, Grad Sch Arts & Sci, Program Virol, Cambridge, MA 02138 USA

[10] Dana Farber Brigham & Womens Hosp, Merkel Cell Carcinoma Ctr Excellence, Canc Ctr, Boston, MA 02115 USA

[11] Vienna Healthcare Grp, Dept Dermatol, A-1130 Vienna, Austria

[12] Sigmund Freud Univ Vienna, Fac Med, A-1020 Vienna, Austria

[13] Techn Univ Munich, Sch Med, Dept Dermatol & Allergy, D-81675 Munich, Germany

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

来源：

SCIENCE ADVANCES | 2024年 / 10卷 / 03期

基金：

美国国家卫生研究院;

关键词：

EXPRESSION; BLOCKADE; RECEPTOR; APOPTOSIS; CANCER; MICROENVIRONMENT; POLYOMAVIRUS; METASTASIS; MODULATION; RESISTANCE;

D O I：

10.1126/sciadv.adi2012

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, we identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis. Our results identify an MCC-PD-1-mTOR-mtROS axis as a tumor growth-accelerating mechanism, the blockade of which might contribute to clinical response in patients with MCC.

引用

页数：16

共 65 条

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