Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations

被引：254

作者：

Kugel, Curtis H., III ^{[1
]}

Douglass, Stephen M. ^{[1
]}

Webster, Marie R. ^{[1
]}

Kaur, Amanpreet ^{[1
,2
]}

Liu, Qin ^{[1
]}

Yin, Xiangfan ^{[1
]}

Weiss, Sarah A. ^{[3
]}

Darvishian, Farbod ^{[4
]}

Al-Rohil, Rami N. ^{[5
,6
]}

Ndoye, Abibatou ^{[1
,2
]}

Behera, Reeti ^{[1
]}

Alicea, Gretchen M. ^{[1
,2
]}

Ecker, Brett L. ^{[1
]}

Fane, Mitchell ^{[1
]}

Allegrezza, Michael J. ^{[1
]}

Svoronos, Nikolaos ^{[1
]}

Kumar, Vinit ^{[1
]}

Wang, Daniel Y. ^{[5
,6
]}

Somasundaram, Rajasekharan ^{[1
]}

Hu-Lieskovan, Siwen ^{[7
]}

Ozgun, Alpaslan ^{[8
]}

Herlyn, Meenhard ^{[1
]}

Conejo-Garcia, Jose R. ^{[8
]}

Gabrilovich, Dmitry ^{[1
]}

Stone, Erica L. ^{[1
]}

Nowicki, Theodore S. ^{[7
]}

Sosman, Jeffrey ^{[9
]}

Rai, Rajat ^{[10
,11
]}

Carlino, Matteo S. ^{[10
,11
]}

Long, Georgina V. ^{[10
,11
]}

Marais, Richard ^{[12
]}

Ribas, Antoni ^{[7
]}

Eroglu, Zeynep ^{[8
]}

Davies, Michael A. ^{[13
]}

Schilling, Bastian ^{[14
]}

Schadendorf, Dirk ^{[15
]}

Xu, Wei ^{[16
]}

Amaravadi, Ravi K. ^{[16
]}

Menzies, Alexander M. ^{[10
,11
]}

McQuade, Jennifer L. ^{[13
]}

Johnson, Douglas B. ^{[5
,6
]}

Osman, Iman ^{[3
]}

Weeraratna, Ashani T. ^{[1
]}

机构：

[1] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA

[2] Univ Sci, Philadelphia, PA USA

[3] NYU, Sch Med, Dept Med, New York, NY USA

[4] NYU, Sch Med, Dept Pathol, New York, NY USA

[5] Vanderbilt Univ, Med Ctr, Nashville, TN USA

[6] Vanderbilt Ingram Canc Ctr, Nashville, TN USA

[7] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[8] H Lee Moffitt Canc Ctr & Res Inst, 12902 USF Magnolia Dr, Tampa, FL USA

[9] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

[10] Melanoma Inst Australia, Sydney, NSW, Australia

[11] Univ Sydney, Westmead & Blacktown Hosp, Sydney, NSW, Australia

[12] Univ Manchester, Canc Res UK Manchester Inst, Manchester, Lancs, England

[13] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[14] Univ Hosp Wurzburg, Dept Dermatol Venereol & Allergol, Wurzburg, Germany

[15] Univ Duisburg Essen, Dept Dermatol, West German Canc Ctr, Essen, Germany

[16] Hosp Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA

来源：

CLINICAL CANCER RESEARCH | 2018年 / 24卷 / 21期

关键词：

METASTATIC MELANOMA; CANCER-IMMUNOTHERAPY; UNTREATED MELANOMA; ESTABLISHED TUMORS; PD-1; BLOCKADE; IMMUNE-SYSTEM; OLD-AGE; THERAPY; IPILIMUMAB; MEMORY;

D O I：

10.1158/1078-0432.CCR-18-1116

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1. Experimental Design: Weanalyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies. Results: Patients over the age of 60 respondedmore efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8(+): Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice. Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. (C) 2018 AACR.

引用

页码：5347 / 5356

页数：10

共 18 条

[11] High tumor mutational burden and T-cell activation are associated with long-term response to anti-PD1 therapy in Lynch syndrome recurrent glioblastoma patient
Anghileri, Elena
Di Ianni, Natalia
Paterra, Rosina
Langella, Tiziana
Zhao, Junfei
Eoli, Marica
Patane, Monica
Pollo, Bianca
Cuccarini, Valeria
Iavarone, Antonio
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[12] A multi-omic single cell sequencing approach to develop a CD8 T cell specific gene signature for anti-PD1 response in solid tumors
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Papillon-Cavanagh, Simon
Tang, Hao
Wang, Shiliang
Stromko, Caitlyn
Ho, Ching-Ping
Soni-Sheth, Sonal
Vasquez-Grinnell, Steven
Broz, Miranda L.
Tenney, Daniel J.
Wichroski, Michael J.
Walsh, Alice M.
Hu, Yanhua
Benci, Joseph L.
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Mahnke, Yolanda D.
Saqr, Areej
Hazenfeld, Staci
Brady, Rebecca C.
Roederer, Mario
Subbramanian, Ramu A.
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Appay, Victor
Fastenackels, Solene
Katlama, Christine
Ait-Mohand, Hocine
Schneider, Luminita
Guihot, Amelie
Keller, Michael
Grubeck-Loebenstein, Beatrix
Simon, Anne
Lambotte, Olivier
Hunt, Peter W.
Deeks, Steven G.
Costagliola, Dominique
Autran, Brigitte
Sauce, Delphine
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Nunez, Nicolas Gonzalo
De La Rochere, Philippe
Pinto, Anais
Denizeau, Jordan
Alonso, Ruby
Niborski, Leticia Laura
Lantz, Olivier
Sedlik, Christine
Piaggio, Eliane
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Inaba, Muneo
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Heeren, A. M.
Rotman, J.
Stam, A. G. M.
Pocorni, N.
Gassama, A. A.
Samuels, S.
Bleeker, M. C. G.
Mom, C. H.
Zijlmans, H. J. M. A. A.
Kenter, G. G.
Jordanova, E. S.
de Gruijl, T. D.
JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2019, 7
[18] Anti-CD49d Ab treatment ameliorates age-associated inflammatory response and mitigates CD8+ T-cell cytotoxicity after traumatic brain injury
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Ford, Kacie P.
Islam, Mecca B. A. R.
Wan, Hanxiao
Han, Hyebin
Ramakrishnan, Abhirami
Brown, Ryan J.
Villanueva, Veronica
Wang, Yidan
Davis, Booker T.
Weiss, Craig
Cui, Weiguo
Gate, David
Schwulst, Steven J.
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