Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours

被引：95

作者：

Brenner, Ellen ^{[1
]}

Schoerg, Barbara F. ^{[2
]}

Ahmetlic, Fatima ^{[3
,4
]}

Wieder, Thomas ^{[1
]}

Hilke, Franz Joachim ^{[5
]}

Simon, Nadine ^{[1
]}

Schroeder, Christopher ^{[5
]}

Demidov, German ^{[5
]}

Riedel, Tanja ^{[3
]}

Fehrenbacher, Birgit ^{[1
]}

Schaller, Martin ^{[1
]}

Forschner, Andrea ^{[1
]}

Eigentler, Thomas ^{[1
]}

Niessner, Heike ^{[1
]}

Sinnberg, Tobias ^{[1
]}

Boehm, Katharina S. ^{[1
]}

Hoemberg, Nadine ^{[3
,4
]}

Braumueller, Heidi ^{[1
]}

Dauch, Daniel ^{[6
,7
]}

Zwirner, Stefan ^{[6
]}

Zender, Lars ^{[6
,7
,8
]}

Sonanini, Dominik ^{[2
,6
]}

Geishauser, Albert ^{[3
,4
]}

Bauer, Juergen ^{[1
]}

Eichner, Martin ^{[9
]}

Jarick, Katja J. ^{[10
]}

Beilhack, Andreas ^{[10
]}

Biskup, Saskia ^{[8
,11
,12
]}

Doecker, Dennis ^{[1
,11
,12
]}

Schadendorf, Dirk ^{[7
,13
]}

Quintanilla-Martinez, Leticia ^{[8
,14
]}

Pichler, Bernd J. ^{[2
,8
]}

Kneilling, Manfred ^{[1
,2
,8
]}

Mocikat, Ralph ^{[3
,4
]}

Roecken, Martin ^{[1
,7
,8
]}

机构：

[1] Univ Tubingen, Dept Dermatol, D-72076 Tubingen, Germany

[2] Univ Tubingen, Werner Siemens Fdn, Lab Preclin Imaging & Imaging Technol, Dept Preclin Imaging & Radiopharm, D-72076 Tubingen, Germany

[3] Helmholtz Zentrum Munchen, Inst Mol Immunol, D-81377 Munich, Germany

[4] Helmholtz Zentrum Munchen, Eigenstandige Forschungseinheit Translat Mol Immu, D-81377 Munich, Germany

[5] Univ Tubingen, Inst Med Genet & Appl Genom, D-72076 Tubingen, Germany

[6] Univ Hosp Tubingen, Dept Med Oncol & Pneumol, D-72076 Tubingen, Germany

[7] German Canc Res Ctr, German Canc Res Consortium DKTK, D-69120 Heidelberg, Germany

[8] Cluster Excellence iFIT EXC 2180 Image Guided & F, D-72076 Tubingen, Germany

[9] Univ Tubingen, Inst Clin Epidemiol & Appl Biometry, D-72076 Tubingen, Germany

[10] Wurzburg Univ, Dept Med 2, D-97078 Wurzburg, Germany

[11] Ctr Genom & Transcript CeGaT GmbH, D-72076 Tubingen, Germany

[12] Practice Human Genet, D-72076 Tubingen, Germany

[13] Univ Duisburg Essen, West German Canc Ctr, Univ Hosp, Dept Dermatol, D-45147 Essen, Germany

[14] Univ Tubingen, Inst Pathol, D-72076 Tubingen, Germany

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

CD4(+) T-CELLS; PD-1; BLOCKADE; CHECKPOINT BLOCKADE; IMMUNOTHERAPY; MELANOMA; RESISTANCE; RNA; SURVEILLANCE; MECHANISMS; RESPONSES;

D O I：

10.1038/s41467-020-14987-6

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：

Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16(Ink4a)/p19(Arf) (Cdkn2a) or p21(Cip1) (Cdkn1a) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication.

引用

页数：19

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