CANCERDISCOVERY CONTENTS

ii | CANCER DISCOVERY�AUGUST 2016 www.aacrjournals.org

AUGUST 2016 ≠ VOLUME 6 ≠ NUMBER 8

M.P. De Macedo, J.L. Austin-Breneman, H. Jiang, Q. Chang, S.M. Reddy, W.-S. Chen, M.T. Tetzlaff, R.J. Broaddus, M.A. Davies, J.E. Gershenwald, L. Haydu, A.J. Lazar, S.P. Patel, P. Hwu, W.-J. Hwu, A. Diab, I.C. Glitza, S.E. Woodman, L.M. Vence, I.I. Wistuba, R.N. Amaria , L.N. Kwong, V. Prieto, R.E. Davis, W. Ma, W.W. Overwijk, A.H. Sharpe, J. Hu, P.A. Futreal, J. Blando, P. Sharma, J.P. Allison, L. Chin, and J.A. Wargo

Précis: Adaptive immune profi les in

early on-treatment tumor biopsies are

predictive of response and identify

potential mechanisms of resistance to

CTLA4/PD-1 blockade.

See commentary, p. 818

High-Level Clonal FGFR Amplifi cation and Response to FGFR Inhibition in a Translational Clinical Trial . . . . . . . . . 838

A. Pearson, E. Smyth, I.S. Babina, M.T. Herrera-Abreu, N. Tarazona, C. Peckitt, E. Kilgour, N.R. Smith, C. Geh, C. Rooney, R. Cutts, J. Campbell, J. Ning, K. Fenwick, A. Swain, G. Brown, S. Chua, A. Thomas,S.R.D. Johnston, M. Ajaz, K. Sumpter, A. Gillbanks, D. Watkins, I. Chau, S. Popat, D. Cunningham, and N.C. Turner

Précis: Tumors with high copy-number

FGFR2 amplifi cation exhibit oncogene

addiction with dependence on FGFR-

mediated PI3K–AKT signaling, creating

sensitivity to FGFR inhibition.

Obesity-Induced Infl ammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy . . . . . . . . . . . . . . .852

J. Incio, H. Liu, P. Suboj, S.M. Chin, I.X. Chen, M. Pinter, M.R. Ng, H.T. Nia, J. Grahovac, S. Kao, S. Babykutty, Y. Huang, K. Jung, N.N. Rahbari, X. Han, V.P. Chauhan, J.D. Martin, J. Kahn, P. Huang, V. Desphande, J. Michaelson, T.P. Michelakos, C.R. Ferrone, R. Soares, Y. Boucher, D. Fukumura, and R.K. Jain

Précis: Obesity promotes PDAC growth and

chemoresistance via a proinfl ammatory,

profi brotic mechanism that may be reversed

by angiotensin-II type-1 receptor blockade.

See commentary, p. 821

RESEARCHARTICLES

Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . . 803

Important news stories affecting the community . . . . . . . . . . 808

Reconstituting the Human Immune System . . . . . . . . . . . . . . . . 812

Selected highlights of recent articles of exceptional signifi cance from the cancer literature . . . . . . . . . . . . . . 813

For more News and Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.

In The Spotlight

Checkpoint Immunotherapy: Picking a Winner . . . . . . . . . . . . . . . 818

M.W.L. Teng, R. Khanna, and M.J. Smyth

See article, p. 827

Adipocytes and Neutrophils Give a Helping Hand to Pancreatic Cancers . . . . . . . . . . . . 821

V. Bronte and G. Tortora

See article, p. 852

Genomic Amplifi cations Cause False Positives in CRISPR Screens . . . . 824

A. Sheel and W. Xue

See article, p. 900

See article, p. 914

Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade . . . . . . . . . . 827

P.-L. Chen, W. Roh, A. Reuben, Z.A. Cooper,C.N. Spencer, P.A. Prieto, J.P. Miller, R.L. Bassett, V. Gopalakrishnan, K. Wani,

IN THIS ISSUE

NEWSIN BRIEF

NEWSIN DEPTH

RESEARCH WATCH

ONLINE

VIEWS

RESEARCHBRIEF

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AUGUST 2016�CANCER DISCOVERY | iii

Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression . . . 870

M.M. Kaneda, P. Cappello, A.V. Nguyen, N. Ralainirina, C.R. Hardamon, P. Foubert, M.C. Schmid, P. Sun, E. Mose, M. Bouvet, A.M. Lowy, M.A. Valasek, R. Sasik, F. Novelli, E. Hirsch, and J.A. Varner

Précis: Inhibition of PI3Kγ expressed by tumor-

associated macrophages restores antitumor

CD8+ T-cell responses and suppresses pancreatic

cancer growth and metastasis in mice.

GM-CSF Mediates Mesenchymal–Epithelial Cross-talk in Pancreatic Cancer . . . . . . . . . 886

M. Waghray, M. Yalamanchili, M. Dziubinski, M. Zeinali, M. Erkkinen, H. Yang, K.A. Schradle, S. Urs, M. Pasca Di Magliano, T.H. Welling, P.L. Palmbos, E.V. Abel, V. Sahai, S. Nagrath, L. Wang, and D.M. Simeone

Précis: Expression of GM-CSF by cancer-associated

mesenchymal stem cells promotes pancreatic ductal

adenocarcinoma growth and metastasis.

CRISPR Screens Provide a Comprehensive Assessment of Cancer Vulnerabilities but Generate False-Positive Hits for Highly Amplifi ed Genomic Regions . . . . . . . . . . 900

D.M. Munoz, P.J. Cassiani, L. Li, E. Billy, J.M. Korn, M.D. Jones, J. Golji, D.A. Ruddy, K. Yu, G. McAllister,

A. DeWeck, D. Abramowski, J. Wan, M.D. Shirley, S.Y. Neshat, D. Rakiec, R. de Beaumont, O. Weber,A. Kauffmann, E.R. McDonald III, N. Keen, F. Hofmann, W.R. Sellers, T. Schmelzle, F. Stegmeier, and M.R. Schlabach

Précis: CRISPR/Cas9-based screens identify

more essential cancer genes than RNAi-based

screens, including false-positive hits in targeted

regions with genomic amplifi cations.

See commentary, p. 824

See related article, p. 914

Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting . . . . . . . . . . . . . . 914

A.J. Aguirre, R.M. Meyers, B.A. Weir, F. Vazquez, C.-Z. Zhang, U. Ben-David, A. Cook, G. Ha, W.F. Harrington, M.B. Doshi, M. Kost-Alimova, S. Gill, H. Xu, L.D. Ali, G. Jiang, S. Pantel, Y. Lee, A. Goodale, A.D. Cherniack, C. Oh, G. Kryukov, G.S. Cowley, L.A. Garraway, K. Stegmaier, C.W. Roberts, T.R. Golub, M. Meyerson, D.E. Root, A. Tsherniak, and W.C. Hahn

Précis: CRISPR/Cas9 targeting reduces cancer cell

proliferation and survival in a gene-independent

manner based on target loci copy number.

See commentary, p. 824

See related article, p. 900

Pearson and colleagues performed a translational clinical trial in which

patients with FGFR alterations were treated with the pan-FGFR inhibitor

AZD4547. Responses occurred in 12.5% of patients with FGFR1-amplified

breast cancer, and 33% patients with FGFR2-amplified gastroesophageal

cancer. High-level, but not low-level, copy-number amplification of FGFR2

was associated with response to AZD4547, and was detectable in the plasma

DNA of responding patients. FGFR1- and FGFR2-amplified cells both exhibited

oncogene addiction with dependence on MAPK signaling, and high-level FGFR2-

amplified cells also exhibited a unique dependence on FGFR-mediated PI3K–AKT

signaling. These findings indicate that FGFR inhibitors may be more effective in tu-

mors with high-level FGFR amplification and may guide clinical development of in-

hibitors targeting FGFR or other amplified receptor tyrosine kinases. For details,

please see the article by Pearson and colleagues on page 838.

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