i
`
`f
`
`=
`OSha es
`ai
`a
`Cancerresearch.
`v.74, no. 7 (Apr. 1 2014)
`GeneralCollection
`W1 CA688
`4-04-11 09:18:18
`2014-0
`
`:
`
`A
`
`.
`
`®
`
`a.
`
`rd
`
`*
`
`t a
`e
`os -
`@
`se"
`*» *~
`
`\
`
`a.
`
`:
`
`a
`
`°
`
`a
`
`.
`
`©
`
`Y
`
`>
`
`=~‘
`‘
`a ’
`April 1,.2014
`= Volume 74
`Number za
`on
`.
`
`'
`
`Ke *e-
`
`EZ]
`
`:
`re é
`r % ‘
`=
`F
`-
`te
`*
`le ‘ Q
`EM NATIONAL
`;
`~~
`*
`PROPERTY OF THE
`-*,. = 2?
`.
`LIBRARY OF
`‘: "8
`
`. fe ' MEDICS§=—MEDICINE,
`é Yvue¥ atOe
`i? 2s -
`,
`>
`
`»
`
`
`
`-
`
`:
`
`i
`
`
`
`
`=o il
`Ih
`UNIV. CHICAGO EX. 2014
`=| MNas
`
`
`
`
`
`
`=o INDEXED
`
`
`
`“—=1S2062 11
`
`
`
`Genome & Co. v. Univ. of Chicago
`PGR2019-00002
`
`
`
`

`

`
`snare
`wattwhateeePosvigdMtino
`
`
`
`UMlaaecemcee AMERICAN ASSOCI
`
`ATION FOR CANCER RESEARCH
`
`Editor-in-Chief
`George C. Prendergast
`Deputy Editor for
`Meeting Reports
`Mariano Barbacid
`
`Deputy Editor for
`Breaking Advances
`William A. Weiss
`
`Breaking Advances Editors
`Julio A. Aguirre-Ghiso
`Kenneth D. Aldape
`Frances Balkwill
`Paul B, Fisher
`Yael P, Mosse
`Joanna J. Philips
`David J. Robbins
`Deputy Editor for Reviews
`Danny A. Welch
`Reviews Editors
`Suzanne A. Eccles
`Jeremy R. Graff
`Harikrishna Nakshatri
`
`Senior Editors
`Clinical Studies
`Theodore 5, Lawrence
`Integrated Systems & Technologies
`Martin W. Brechbiel
`Trachette L. Jackson
`Sola D. Merajver
`David W. Speicher
`Jolin A. Weinstein
`Microenvironment & Immunology
`Hellmut G. Augustin
`Christophe Gaux
`Maria P. Colombo
`Yes A, DeClerck
`Dmitry |, Gabrilovich
`Korelia Polyak
`Mark J. Smyth
`Molecular & Cellular Pathobiology
`Steven P, Halk
`Joba 0, Carpten
`Junjie Chen
`Mark W. Dewhirst
`Hiroyuki Mano
`Hideyuki Saya
`Prevention & Epidemiology
`Saraswat) Sukumar
`dames A, Cerhan
`Therapeutics, Targets & Chemical Biology
`Robert Clarke
`Antonia 1, Foye
`Janet A, Houghton
`William G. Nelson
`Patrick M. O'Connor
`Yves Pommier
`David B. Solit
`Kenneth 0, Tew
`Tumor & Stem Cell Biology
`Laura E. Benjamin
`David D.L. Bowtell
`Holl A. Brekken
`Myles A. Brown
`Philip W. Hinds
`Naney E. Hynes
`Rakesh Kumar
`Toshikaru Ushiima
`Max Wicha
`
`Editorial Board
`
`Sarki A. Abdulkadir
`Natalie G. Ahn
`Kari Alitalo
`Shrikant Anant
`Alexander R.A. Anderson
`Jeffery Aube
`Leonard H. Augenlicht
`Ali Badache
`Albert S. Baldwin
`Per H. Basse
`Gregory L. Beatty
`William T. Beck
`David G. Beer
`Jurgen Behrens
`Mohamed Bentires-Alj
`Gabriele Bergers
`Zaver Bhujwalla
`William L. Bigbee
`Robert E. Bristow
`Angela MH. Brodie
`Nelson E. Brown
`Ronald J. Bukanovich
`Helen M. Byrne
`Peter T. Campbell
`Christine Canman
`Natasha Caplen
`David P. Carbone
`Alessandra Care
`France Carrier
`Jason S. Carroll
`Timothy C. Chambers
`Mark A.J. Chaplain
`Alain Charest
`Je-Yoe! Cho
`James G. Christensen
`Brock C. Christensen
`Michael Cole
`David V. Conti
`Vittorio Cristini
`Chi Van Dang
`immaculata De Vivo
`Eleftherios P. Diamandis
`J. Alan Diehl
`Dan A. Dixon
`Giulio F. Draetta
`Stefan Duensing
`
`Rick Durrett
`Kristin A. Eckert
`Wafik El-Deiry
`Lee M. Ellis
`Leisha Emens
`Heiko Enderling
`Eric R. Fearon
`Felix Y. Feng
`Napoleone Ferrara
`Stephen W. Fesik
`Barbara Fingleton
`Stuart Forbes
`Heide L. Ford
`David A. Frank
`Stephen Friend
`Simone Fulda
`Craig J. Galban
`Awen M, Gallimore
`Michelle D. Garrett
`Irwin H. Gelman
`Edward P. Gelmann
`David Gius
`Andrew K. Godwin
`Jeremy R. Graff
`Sergei Grivennikov
`Mare J. Gunter
`William C. Hahn
`Kevin M. Haigis
`Christopher Haiman
`Matthias Heikenwalder
`Kristian Helin
`Mary J.C. Hendrix
`Stephan Herzig
`Guo-fu Hu
`Antonio lavarone
`M. Luisa Iruela-Arispe
`David M. Kaetzel
`Antoine E. Karnoub
`Maria Kavallaris
`Khandan Keyomarsi
`Seema A. Khan
`Jan K, Kitajewski
`Rick A. Kittles
`Celina G. Kleer
`Aloysius Klingelhutz
`Natalia Komarova
`
`Sergio A. Quezada
`Derek C. Radisky
`Ajay Rana
`V. Ashutosh Rao
`W. Kimryn Rathmell
`Jeffery C. Rathmell
`Jeremy N. Rich
`Brian |. Rini
`David Roodman
`Julie A. Ross
`Martine F. Roussel
`Julien Sage
`Jann N. Sarkaria
`Robert J. Schneider
`Stephen Schwartz
`Judith Sebolt-Leopold
`Oliver John Semmes
`Michael M. Shen
`le-Ming Shih
`Gail F. Sonenshein
`Douglas R. Spitz
`M. Sharon Stack
`Esta Sterneck
`Chris H. Takimoto
`Joseph R. Testa
`Dan Theodorescu
`Donald J. Tindall
`Claudio Tripodo
`Melissa A. Troester
`Bruce Tromberg
`Thomas TUting
`Cheryl L. Walker
`Sophia S. Wang
`Markus Warmuth
`Jeffrey S. Weber
`Wenyi Wet
`Ralph R. Weichselbaum
`Jedd D. Wolchok
`Cassian Yee
`Hua Yu
`Rugang Zhang
`Wei Zheng
`Weiping Zou
`
`Yutaka Kondo
`Constantinos Koumenis
`Charlotte Kuperwasser
`Natasha Kyprianou
`James V. Lacey
`Lucia Languino
`Elizabeth R. Lawlor
`Sam W. Lee
`Claire E. Lewis
`Da-Qiang Li
`Christopher |. Li
`Mats Ljungman
`M. Scott Lucia
`David Lyden
`Conor C, Lynch
`Philip Maini
`Anirban Maitra
`Carlo C. Maley
`Linda H. Malkas
`Frank C. Marini
`Stephen R. Master
`Andrea M. Mastro
`Massimiliano Mazzone
`Sandra S. McAllister
`Andrew Mellor
`Steven D. Mittelman
`Lindsay M. Morton
`David H. Munn
`Maureen E. Murphy
`Ruth J. Muschel
`Kenneth P. Nephew
`Marian L. Neuhouser
`Daniel Normolle
`Rienk Offringa
`Hideho Okada
`Monilola A. Olayioye
`Gilbert S. Omenn
`Karolina Palucka
`Quintin Pan
`Tej K. Pandita
`Klaus Pantel
`Ben Ho Park
`Marie-France Penet
`Gerd P. Pfeifer
`Kristian Pietras
`Ludmila Prokunina-Olsson
`
`blished iwice a month, one volumeper year, by the American Association tor
`
`v8 5472 (Print): ISSN: 1538-7445 (Online)| is pu
`OSTMASTER: Sendaddress changes to Cancer Rescate I, Member Services,
`Editorial Office: (mer Research [ISSN: 0
`
`Jat Philadelphia, PA, andadditional mailing offices.
`rorg, Copyright 2014 the Amerioan Assoc iationt for Cancer Research, Inc,
`Cancer Research, Ine, Periodicals postagepare
`ado or Email membership@a
`AACR, 619 Chestnut Street, 17th Poor, Philadelphia, PA 1L06-
`Printed an acid free paper i the United States of America
`
`

`

`
`
`4P
`
`
`
`riean AR OW
`rpricemie rch
`
`
`
`AACR Officers
`
`Charles L. Sawyers, President
`Carlos L. Arteaga, President-Elect
`Frank McCormick, Past President
`William N. Hait, Treasurer
`Margaret Foti, Chief Executive
`Officer
`
`Publications
`Committee
`Michael E. Berens
`Gideon M. Bollag
`Michael A. Caligiuri, Chairperson
`Richard M. Caprioli
`Arul M. Chinnaiyan
`Joseph F. Costello
`Chi Van Dang
`Jessica Clague DeHart
`Lisa Diller
`Levi A. Garraway
`John D. Groopman
`Emest T. Hawk
`Sandra J. Horning
`Nancy E. Hynes
`Pasi A. Janne
`Emma M. Lees
`Guillermina Lozano
`Richard M. Marais
`William G. Nelson
`David R. Parkinson
`David Piwnica-Worms
`Robert H. Vonderheide
`
`Publishing Staff
`Publisher
`Christine B. Rullo
`Director, Editorial Operations and
`Managing Editor
`Kelly A, Hadsell
`Assistant Managing Editor
`Jeremy Rosenberg
`Associate Director, Scientific
`Content Development
`Arthur M, Buchberg
`Editorial Staff
`Amir Khalili
`Naima D. Stone
`Timothy Rinehart
`Jen Zimmerman
`Associate Director, Production
`Charlene Squibb
`Production Manager
`Brenda Roberson
`Senior Production Editor,
`Special Features
`Sue Russell
`Director, Electronic Publishing
`Robert Spanier
`Electronic Publishing Staff
`Mary Beth Cunney
`Diane M. Marinelli
`Chris D. Wozniak
`Associate Director,
`Sales and Marketing
`Nicola L. Hill
`Assistant Director,
`Circulation and Fulfillment
`Karola Rac
`Marketing and Creative Services
`Director
`Paul Driscoll
`Design Staff
`Susan Moore
`
`Scope
`Cancer Research publishes original studies, reviews, and
`opinionpieces offering significanceand broad impaet toa
`
`diverse audience.
`The main seope of the journal is
`
`captured in its primary subsections, which focus on
`molecular and cellular pathobiology, Lumor and stem cell
`biology, therapeutics and targets, microenvironment and
`immunology, prevention and epidemiology, and
`integrated systems and technology,
`Cancer Researchis abstracted and/or indexed in
`MEDLINE, Index Medicus, Web of Science,
`seience Citation lndex, Current Contents/Lile Sciences,
`Current Contents/Clinical Medicine, BIOSIS Previews,
`Chemical Abstracts, and Seopus.
`
`Submission of Manuscripts
`Online submission of manuscripts is welcomed at
`http://canmsubmitnet, Before submitting a manuscript,
`please read the Instructions for Authors, which
`is available from the journal's home page at
`hllps//cancerres.aacrjournals.org,
`
`Page Charges
`Accepted manuscripts will be published with the
`understanding that the author(s) will pay a charge of $95
`per printed page for articles one to six pages in length;
`S120 per additional page. Discounted charges are available
`for members.
`
`Subscription Information
`AACK Members, Subscription options are print with
`online access or online aecess only, Conmbiet
`Hennhershipeeaderorg ar see bt [puwwwader org, and pe
`Lo the membership page for farther information,
`Institutions. Send site license (ineludes remote and
`proxy server access) inquiries to pubsalesenaeror or
`contact your local agent,
`
`Nonmember tndividuals. Subscriptions inelide print
`
`VeTsion WHT ontine aecess, Contacts listed below are for
`nonmember inelividinal stilise rip abies.
`Japon
`Sem orders anid inquiries to one of the following conbiets;
`CSTIPPOPLROTMITIZAETICO, Hilagp.Swels.COnn
`RIP eebscacconk jounnailir kick aniyaeo. jp
`SOO TSO |
`
`USA and Test of World Goselading fapan)
`Publications Sales & Marketing, American Association tor
`Cineer Research, 615 Chestant Street. Dtvilivederlyobiiin, DN
`L010: phone 1-855-741-4607: email pubsalesmeanenoarg,
`International subscriptions inchide cost of surkace mail
`Expedited mailing is available, Contact American
`Association for Cancer Research tor rates.
`
`Changeof Address. Send change of address
`notification 60 days in advance and include both old and
`newaddresses. Member subscribers should contact AACK
`Member Services, 615 Chestnut St. 17th Floor,
`Philadelphia,
`PA 19106-4404; email membership@aacrorg,
`Nonmember subscribers should contact Publications
`Sales & Marketing, American Association for Cancer
`Research, 615 Chestnut Street, Philadelphia, PA 19L06:
`email pubsales@aacrorg,
`
`Claims. Claims for missing issues made within 120 days
`of the issue’s publication date will be honored while
`supplies
`last. No credits or refunds will be given if an
`issue is “oul of print” al
`the time of claim. Member
`subscribers should contact membership@aacrorg, phone
`250-9900, fax 215 dO-OP2. Tastititions ane
`
`nonmember subseribers should direct claims to the
`
`American Association for Cancer Research at
`the
`appropriate address above or by e-niail pubsales@aacr,
`ore.
`
`Single Issue Sales. Single issues and back stock of the
`journals may be ordered from the AACK main office by
`calling 866-125-3965 (Loll-free) or 215-440-9800. Price of a
`
`single issue is $60 and includes U.S, surkiee postage.
`Orders outside of the U.S. are $65 and include postage.
`
`Advertising Information
`Inquiries about advertising should be directed to:
`Pharmaceutical Media Ine. 30 Rast 33rd St. 4th Floor,
`NY. NY, LOOL6; Phone: 212-685-5010;
`emiuk Mperlowitz@pminy.com.
`
`Copyright and Permissions
`As a not-for-profit organization incorporated in the
`United States, AACR adheres to US. copyright law(PL 4-
`553), which became effective January 1, L978. The law
`stipulates that copyright for works is vested in the author
`from the moment of creation and remains the property of
`the
`author until legally transferred. Authors who wish to
`publish articles and other material in AACR journals
`must formally transfer copyright lo AACR, The copyright
`transfer form must be signed by all authors before
`AACK can proceed with publication.
`
`After a manuscript has been deemed potentially
`acceptable, all authors on the manuseript will be
`requested to complete
`
`an online copyright Lranster agreement through the
`SmartSubmit system. The AACK journals will not publish
`a paper unless forms have been properly completed and
`retnrned by ALL authors.
`
`Fo read the complete version of AACK's Copyright
`aod Pormnissions Policy, please visil
`iltps/ /Gineerresamerjournals.ore/site/mise ior,
`shtmlecopyright permissions. Chis policy inelides tiethes
`Wihormation on authors rights ob isage, permission
`requests From third parties, free aecess to AACT journals,
`foniding ageney require ments, ad the National fstitibes
`Of Health) Public \ecess Motiey,
`
`No responsibility is aceepled by the Editors or
`
`
`SAAC, Ine. for the op
`Sexpressed by
`contributors or for the content af the
`advertisements,
`
`American Association for Cancer esearch
`615 Chestout Street
`Philadelphia, PA T9TOG-d104
`Phone: 205-9300
`Fax:
`21h b10-9954
`
`Eomaik cancerresqaacrcrg,
`Website: wwwaiaerorg
`
`

`

`
`
`*
`Jor Gance¥Research .
`ae J
`<< %
`
`April 1, 2014 ¢ Volume 74 ¢ Number 7
`
`BREAKING ADVANCES
`
`MICROENVIRONMENT AND IMMUNOLOGY
`
` clinerican Associlion
`
`1883
`
`Highlights from Recent Cancer Literature
`
`1924
`
`REVIEWS
`
`1885
`
`1890
`
`fe
`
`Obesity and Cancer: A Gut Microbial
`Connection
`Naoko Ohtani, Shin Yoshimoto, and Eiji Hara
`
`Transforming Growth Factor-[ as a
`Therapeutic Target in Hepatocellular
`Carcinoma
`Gianluigi Giannelli, Erica Villa, and Michael Lahn
`
`PRIORITY REPORT
`
`1895
`
`A CommonCancer-Associated DNA Polymerase
`¢ Mutation Causes an Exceptionally Strong
`Mutator Phenotype, Indicating Fidelity Defects
`
`Distinct from Loss of Proofreading
`Daniel P. Kane and Polina V. Shcherbakova
`
`Precis: This study describes the functional consequences
`of the most frequent DNA polymerase variant linked to
`colorectal and endometrial cancer, challenging the recently
`Jorwardedidea that hypermutated human cancers must
`result fromloss of exonuclealytic proofreading.
`
`INTEGRATED SYSTEMS AND TECHNOLOGIES
`
`VISTA Is an Immune Checkpoint Molecule for
`Human T Cells
`J. Louise Lines, Eirini Pantazi, Justin Mak,
`Lorenzo FP. Sempere, Li Wang, Samucl O'Connell,
`Sabrina Ceeraz, Arief A. Suriawinata, Shaofeng Yan,
`Mare 5. Ernstoff, and Randolph Noelle
`Precis: Therapeutic inactivation of CTLA-t-related
`molecules like VISTA may have enormouspotential for
`generalized immunotherapy ofcancer.
`
`1933.
`
`1945
`
`VISTA Regulates the Development of Protective
`Antitumor Immunity
`Isabelle Le Mercier, Wenna Chen, Janet L. Lines,
`Maria Day, Jiannan Li, Petra Sergent,
`Randolph J. Noelle, and Li Wang,
`Precis: This study offers a prectinical proof-of-concept to
`evaluate the efficacy and mechanisms of action ofa
`VWSTA-targeting antibody in multiple tumor modets,
`
`Vaccine-Mediated Immunotherapy Directed
`against a Transcription Factor Driving the
`Metastatic Process
`Andressa Ardiani, Sofia R. Gameiro, Claudia Palena,
`Duane H. Hamilton, Anna Kwilas, Thomas FH. King,
`leffrey Schlom, and James W. Hodge
`Précis: This study affers a preclinical proafofconcept for
`an antinetastasis vaccine targeting Twist, a transcription
`factor that promotes metastasis and drug resistance in
`many tumor types,
`
`1902
`Ky
`
`Noninvasive Quantification of Solid Tumor
`Microstructure Using VERDICT MRI
`Eletheria Panagiotaki, Simon Walker-Samuel,
`Bernard Siow, S. Peter Johnson, Vineeth Rajkumar,
`R. Barbara Pedley, Mark F. Lythgoe, and
`Daniel C. Alexander
`
`Precis: This article highlights the superior qualities of a
`novel noninvasive imaging method to monitor tumor
`development andtherapeutic responsein preclinical models.
`
`1958
`
`IT Lymphocytes Restrain Spontaneous
`Metastases in Permanent Dormancy
`Irene Romera, Cristina Garrido, Ignacio Algarra,
`Antonia Collado, Federico Garrido, and
`Angel M. Garcia-Lora
`Precis: This study describes a prectinical model for
`dormant metastases controlled by the immune systent an
`understanding ofwhich maylead to newinsightsinte howto
`extend survival by blocking relapses ofmetastatic cancer.
`1913=Apoptosis Imaging for Monitoring DR5
`1969s
`IL-17A Producedby 76 T Cells Promotes Tumor
`Antibody Accumulation and
`Pharmacodynamics in Brain Tumors
`Growth in Hepatocellular Carcinoma
`Shoubao Ma, Qiao Cheng, Yileng Cai, Hluanle Gong,
`Noninvasively
`Thomas G. Weber, Franz Osl, Anja Renner,
`Yan Wu,Xiao Yu, Liyun Shi, Depei Wu, Chen Dong,
`Thomas Poschinger, Stefanie Galban,
`and Haiyan Liu
`Alnawaz Rehemtulla, and Werner Scheuer
`Precis: Thesefindings offer new insights into how the pro-
`inflammatory cytokine H.-17A influences (amor inimunity,
`with potential implications for the development oftumor
`jnannunotherapy.
`
`Precis: This prectinical study reports a method to quantify
`antibody accumulation and pharmacedyaamics in brain
`tumors, where delivery after systemic administrationis aften
`difficult to assess, offering a holistic in vivo approach to
`assess CNS-fargeting drugs,
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`

`

`"+a6
`
`~~
`
`“~\e
`
`- M
`
`2038
`
`Tumor-Infiltrating Myeloid Cells Activate
`D4 /Noteh/TGE-[3 Signaling to Drive
`Malignant Progression
`Hidetaka Ohnuki, Kan Jiang, Dunrut Wang,
`Ombretta Salvucci, Hyeongil Kwak,
`David Sanchez-Martin, Dragan Maric, and
`Giovanna Tosato
`
`Precis: This study describes a mycloid cell-carcinoma
`signaling network that links the tumor microcnvironment
`in new ways with famor growth, highlighting opportunities
`fo farget timmors where tis network is active.
`
`THERAPEUTICS, TARGETS, AND CHEMICAL
`BIOLOGY
`
`2050
`
`Ky
`
`2073
`
`CBP Loss Cooperates with PTEN
`Haploinsufficieney to Drive Prostate Cancer:
`Implications for Epigenetic Therapy
`Liya Ding, Shuai Chen, Ping Liu, Yunqian Pan,
`Jian Zhong, Kevin M. Regan, Liguo Wang,
`Chunrong, Yu, Anthony Rizzardi, Liang, Cheng,
`Jun Zhang, Stephen C. Schmechel, John C. Cheville,
`Jan Van Deursen, DonaldJ. Tindall, and
`Haojie Huang
`
`Precis: These results suggest newinsights into prostate
`cancer etiology, establishing a central role for fistone
`modification and providing a rationaleforclinical
`evaluation of epigenctic-targeted therapy in prostate
`cancer patients,
`
`Novel Mechanistic Insights into Ectodomain
`Shedding of EGFR Ligands Amphiregulin and
`‘TGF-c: Impact on Gastrointestinal Cancers
`Driven by Secondary Bile Acids
`Nagaraj S. Nagathihalli, Yugandhar Beesetty,
`Wooin Lee, M. Kay Washington, Xi Chen,
`A. Craig Lockhart, and Nipun B. Merchant
`Precis: Thesefindings define an EGF-related signaling
`pathwaythat mediatesthe oncogenic effects of secondary
`bile acids in gastrointestinal cancers, the targeting of
`which may enhance therapeutic responses,
`
`Bioluminescent Imaging of HPV-Posilive
`Oral Tumor Growth and Its Response to
`Image-Guided Radiotherapy
`Rong, Zhong, Matt Pytynia, Charles Pelizzari, and
`Michael Spiotto
`Precis: More rapid visualization of HPV pasitive areal
`tamer growth will assist the development of
`chemoatherapentic and radiotherapoutic stratevios lo ston,
`Hes rapidly wrowine discese,
`
`OLECULAR AND CELLULAR
`PATHOBIOLOGY
`
`1983
`
`1996
`
`2006
`
`f-Catenin Inhibitor ICAT Modulates the
`Invasive Motility of Melanoma Cells
`MelanieJ. Domingues, Florian Rambow,
`Bastien Job, Laura Papon, Wanguo Liu,
`Lionel Larue, and Jacky Bonaventure
`Precis: [CAT inhibition reduces the mesenchymal-
`amoeboid transition invalved in invasive cancer cell
`
`motility, limiting metastasis formation.
`
`Sre Kinase Is a Novel Therapeutic Target in
`Lymphangioleiomyomatosis
`Alexey Tyryshkin, Abhisek Bhattacharya, and
`N. Tony Essa
`Pi
`Precis: This study provides a mechanistic rationale to
`inunediately reposition the use of Sre inhibitors currently
`in clinical trials for the treatment of malignancies
`associated with mutation ofthe tumor suppressor gene
`TSC2.
`
`PP2A-B553 Antagonizes Cyclin El Proteolysis
`and Promotes Its Dysregulation in Cancer
`YingMeei Tan, Dahui Sun, Weijian Jiang,
`Kathleen Klotz-Noack, Ajay A. Vashisht,
`James Wohlschlegel, Martin Widschwendter, and
`Charles Spruck
`Precis: As a candidate therapeutic target, overexpressed
`cyclin EL is a driving force of hormone-independent
`growth, genetic instability, and progression of ‘triple
`negative” breast cancers dnd other aqgeressive cancers,
`
`2015
`
`
`LRIL-T Governs Vital Transcriptional
`Programs in Endocrine-Sensilive and
`-Resistant Breast Cancer Cells
`
`2026
`
`Stéphanie Bianco, Mylene Brunelle, Matka fangal,
`Luca Maynant, and Nicolas Gayry
`Preeis: (his study shows how the nuclear receptor LRIE
`modulates the sensitivity of breast cancer colls ta
`difiestraven therapy, siimeesting nen: insights fate how
`resistance may crteree to font treatment cffectiveness,
`
`Latency-Associated Nuclear Antigen of Kaposi
`Sarcoma—Associated Herpesvirus Promotes
`
`Angiogenesis through Targeting Notch
`Signaling Effector Hey!
`Xing Wang, Zhiheng He, Tian Xia, Xiaotan Li,
`Deguang Liang, Nianzhi Lin, Hao Wen, and Ke Lan
`
`Precis: These findings identify a therapeutic target for
`treatment of Kapost sarcoma, a cancer best known jorits
`association with ALDS patients at highest risk of this
`herpesvirus-driven disease.
`
`vi
`
`

`

`.
`
`<—
`
`we f
`
`+ Rankevtgancents,
`
`TUMOR AND STEM CELL BIOLOGY
`
`2106
`
`2082
`
`2094
`
`Small GTPase Rhok/Rnd3 Is a Critical
`Regulator of Notch! Signaling
`Zehua Zhu, Kristina Todorova, Kevin K. Lee,
`Jun Wang, Eunjeong Kwon, Ivan Kehayov,
`Hyung-Gu Kim, Vihren Kolev, G. Paolo Dotto,
`Sam W. Lee, and Anna Mandinova
`
`Precis: These findings describe an important regulatory
`feedback on a key tumor suppressor pathway that may
`have a pivotal role in epithelial tumors.
`
`Attenuation of microRNA- 126 Expression That
`Drives CD34'38 Stem/Progenitor Cells in
`Acute Myeloid Leukemia Leads to Tumor
`Eradication
`David C, de Leeuw, Fedor Denkers,
`Marjolein C. Olthof, Arjo P. Rutten, Walter Pouwels,
`Gerrit Jan Schuurhuis, Gert J, Ossenkoppele, and
`Linda Smit
`
`Precis: These findings define mift-126 as a therapeutic
`Jocus to specifically eradicate stenv-like cells in acute
`myeloid leukemiasthat tend to relapsein patients despite
`carly positive responses to chemotherapy.
`
`NOTCHSSignaling Regulates MUSASHLI
`Expression in Metastatic Colorectal Cancer
`Cells
`Anna Pasto, Valentina Serafin, Giorgia Pilotto,
`Claudia Lago, Chiara Bellio, Livio Trusolino,
`Andrea Bertotti,Timothy Hoey, Michelina Plateroti,
`Giovanni Esposito, Marica Pinazza, Marco Agostini,
`Donato Nitti, Alberto Amadori, and
`Stefano Indraccolo
`
`Precis: These findings point to a specific inhibition of
`NOTCH2/3, rather than NOTCHI, as a strategy for
`attacking cancerstem-like cells in metastatic colon cancer.
`
`shRNA Kinome Screen Identifies TBKI as a
`Therapeutic Target for HER2) Breast Cancer
`Tao Deng, Jeff C. Liu, Philip E.D. Chung,
`David Uehling, Ahmed Aman, BabuJoseph,
`Troy Ketela, Zhe Jiang, Nathan F. Schachter,
`Robert Rottapel, Sean L. Egan, Rima Al-awar,
`Jason Moffat, and Eldad Zacksenhaus
`
`Precis: These results identify a novel target to improve
`treatment of HER2-positive breast cancer trough
`leveraging existing anti-HER2 therapy.
`
`2119
`
`CORRECTION
`
`2131
`
`Correction: Epithelial Junction Opener JO-1
`Improves Monoclonal Antibody Therapy of
`Cancer
`
`Mig AC icon indicates Author Choice
`For more information please visit www.aacrjournals.org
`
`ABOUT THE COVER
`
`Numerous reports have now demonstrated that the epithelial-to-mesenchymal transition (EMT)
`
`
`
`process is involved in solid tumor progression, metast
`and drug resistance. Several
`transcription factors have been implicated as drivers oF EMTand metastatic progression, including
`
`Twist, which has been shown to be associated with poor prognosis and drug resistance for
`
`
`jinomas and other tumor types. The role of a Twist vaccine in experimental cance
`met
`
`ses has beenprincipally studied in the 401 mammary tumor model, where there is a greater
`than fold inerease in Twist expression in lung metastases (shown) vs. the primary tumor.
`Vi
`ination of mice reduced the size of primary transplanted 471 tumors and had an even greater
`
`
`
`specific
`tumor effeet on hing metastases of the same mice, which was dependent on Twi
`‘These studies provide the rationale for vaccine-induced T-cell-mediated therapy of
`Tvells.
`transcription factors invelved in driving the metastatic process. For details, see article by Ardiani
`and colleagues on page 15,
`
`viliee
`
`4**
`i
`-
`/
`{,t*o
`aetee fOr 5.
`ane "4 aw eT are
`AN Tis ay Biege o)
`itekt nee ie Se 8
`ta Y re zee ‘
`Py20%09
`¥ore
`a,
`
`« pees ’
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`
`
`MicroenvVironment and tmmi nology
`
`
`
`VISTA Regulates the Developmentof Protective Antitumor
`Immunity
`
`Isabelle Le Mercier’, Wenna Chen’, Janet L. Lines’, Maria Day*, Jiannan Li’, Petra Sergent',
`
`Randolph J, Noelle!" and Li Wang!
`
`Abstract
`
`V-domain ly suppressor ol T-cell activation (VISTA) is a novel negative cheekpoint ligand that is homologous
`to PD-LT and suppresses ‘T-cell activation, Uhis study demonstrates the multiple mechanisms whereby VISTA
`relieves negative regulation by hematopoietic cells and enhances protective antitumor immunity, VISTA is highly
`expressed on myeloid cells and Foxpa CD regulatory cells, but not on tamer cells within the tumor
`microenvironment (EME) VISTA monoclonal antibody (mAb) treatment
`increased the number of lumar-
`specie Tocells in the periphery and enhanced the infillration, proliferation, and effector function of tumer
`reactive ‘TP cells within the PME. VISTA blockade altered the suppressive feature of the TME by decreasing the
`presence of monocytic myeloid-derived suppressor cells and imereasing the presence of uctivated dendritic cells
`within the tumor mieroenvironment, Inaddition, VISTA blockadeimpaired the suppressive finction and reduced
`the emergence of tumor-specific Foxp3 CD regulatory T cells. Consequently, VISTA mAb administration as a
`monotherapysignificantly suppressed the growth ofboth transplantable and inducible melanoma, Mitial studies
`explored a combinatorial regimen using VISTA blockade and a peptide-based cancervaccine with TLRagonists as
`adjuvants. VISTA blockade synergized with the vaceineto effectively impair the growth of established tumors. Our
`study therefore establishes a foundation for designing VISTA-targeted approaches eitheras a monotherapyor in
`combination with additional immiune-targeted strategies for cancer immunotherapy, Cancer Ress(7): L9GaAd.
`O2OhE AACR,
`
`Introduction
`
`Limune responses against cancer are negatively regulated
`by multiple cheekpoints, including CPLA, PD-LL/PD-1, and
`B7-T pathways. Targeting of these negative immune regula
`tors has proved to be a clinically effective strategy to enhance
`humor-specific immune responses (1, 2).
`The eritieal
`role of T CTLA in suppressing tumor
`specie immunity was demonstrated when antibody-medi-
`ated CULA( targeting in combination with a cellular vae-
`cine induced regression of established, poorly immunogenic
`Blo melanoma (3).
`(pilimumab, an antivuman CPhA-d4
`monoclonal antibody (mAb), as a monotherapy has proved
`fa exert clinieal benefit
`in late-stage melanoma in patients
`and bas been approved for treating advanced melinoma,
`
`Authors’ Affiliations: ‘Department of Microbiology and Immunology, The
`Geisel School ot Medicine at Dartmouth, The Norris Cotten Cancer Center;
`“mnuNext Ine., Lebanon, New Hampshire; and “Medical Research Coun-
`cll Centre of Transplantation, Guy's Hospital and ‘Department of Immune
`Requlation and Intervention, King’s College London, King's Health Part:
`ners, London, United Kingdom
`
`Note: Supplementary data for this article are available at Cancer Research
`Online (bip://canceres.aacrjournals,arg/),
`
`Corresponding Author: Li Wang, Geisel school of medicine, Rubin Bldg
`764, Norris Cotton Gancer Center, Lebanon, NH 03756, Phone: 603-653-
`6004; Fax: G03-653-990e; E-mail: Li.Wangi@dartrmouth.edu
`doi: 10,1 158/008-5472 .CAN-13-1506
`2014 American Assocation for Cancer Research.
`
`
`
`as well as undergoing early-phase trials for other cancers
`(41-6).
`Programmed death-) (PD-1) and its ligands PD-LL/PD-L2
`represent another immune negative checkpoint axis (7.5). ‘The
`PD-1 pathway downregulates (amor-specitie immunity by
`impairing ‘T-cell responses and promoting the induction ol
`Foxpa! ‘Preas in the periphery (1.9). Blocking the PD 11 /PD-]
`pathway. in conjunction with other immune therapies inhibits
`Inmor progression (10-15). MDX-E106/BMS-930558,
`the
`human @PD-1 mAb, as well as a human @PD-LE mAb, have
`entered clinical trials, and early studies have shown resounding,
`clinical results (16-18).
`Given the success of immune-cheekpoint regulator blockade
`rm
`ook
`and -vaccine-dlicited antitumor
`in improving both endogenous ener cre ee sc
`immuneresponses, identification of additional negative ¢ heek-
`point regulator pathways would likely have inyportant thera:
`peutic implications. We have recently discovered a novel
`immunoglobulin (lg) superfamily ligand, designated V-domain
`Jz Suppressor of T-cell activation (VISTA; Genbank: [No02 181:
`ref 19). VISTA bears homologyto PD-L.L but displays a distinet
`expression pattern. Within the hematopoietic compartment.
`VISTA is constitutively and highly expressed on CD] ips
`myeloidcells, and expressedal lower levels on CD41 Pand CD8-
`‘T cells and Foxp3'
`‘Treys. The human and murine homologs
`share 90%homology, have indistinguishable functional prop-
`erties, and are similarin their lineagerestricted expression (20),
`VISTA expressed on APCs directly suppresses CDT)
`and CDS”
`‘T-cell proliferation and cytokine production (19),
`
`
`
`www. aacrjournals.org
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`AR Diner nedine oLSseRrenine fee CancerResearch
`
`1933
`
`

`

`Le Mercier et al,
`
`We hypothesize that VISTA is a novel negative cheekpoint
`regulator and a promising new target for cancer immunother
`apy. This study has utilized a VISTA-specitic blocking mAb to
`examine the role of VISTA in regulating antitumor immunity.
`Our data show that VISTA ouAb treatment
`impaired the
`suppressive character of the tumor microenvironment (EME)
`and enhanced protective antitumor immunity, Furthermore,
`initial studies exploring a combination regimen ol VISTA
`blockade together with a peptide vaccine show synergistic
`efficacy, As such, our study establishes a foundation lor
`designing optimal
`therapeutic approaches that
`incorporate
`VISTA blockade either as a monotherapy or in combination
`with additional immune-targeted therapies,
`
`Materials and Methods
`
`Mice
`CS7BL/6 mice were from NCL TREE and OH CD trans
`
`genic mice were from the Jackson Laboratory. FoxPa-Ghe
`reporter mice were as described (21) and were generously
`provided by Dr, Alexander Kudensky (University of Washing
`ton School of Medicine, Seattle, WA). The triple transaenic
`
`mice strain Bo.Ce- Bra Plan! "pa (LyreCre/BR') was
`obtained from Dr. Bosenberg (Yale School of Medicine, New
`Haven, CT). Ml animals were maintained in a pathogen-free
`facility al Dartmouth Medical School, AIL animal protocols
`were Institutional Animal Care and Use Committee approved
`al the Dartmouth College.
`
`Tumor models, tumor vaccine, and treatment
`MEMO (300,000), BIGOVA (120,000), aod BLbBLG (18,000)
`
`tumor cells were inoculated on the right thank of female mice.
`Por the PTEN/BRAL melinoiia model, Luror were tneuaced
`
`Materials and Methods are deseribed in detail in the Sup
`plementary Dati
`
`Results
`
`VISTA mAb treatment impairs tumor growth in
`immunogenic transplantable tumor models
`We have previously generated a hamster monoclonal anti
`body (clone [3P3) that neutralizes the suppressive activity of
`VISTA (19) We hypothesized that VISTA mAb-mediated
`blockade would enhance antitumor mune responses. Chis
`hypothesis was tested in murine tumor models. We first
`examined the immunogenicity and defo clearance ob Lbs
`(Supplementary Vie. St), Our data show that mice developed
`strong immune response against
`ISbS and aecumulited high
`levels neutralizing antibodies, which presumably leads to fast
`clearance of (SPS. In fact, afer a week ofcontinuous treatment,
`
`we ean no longer detect any F8h3 in the serum when blood was
`analyzed 24 hours aller cach injection. Our data indicates that
`the most effective window of 1S0S-mediated VISTA blockade
`
`ivive moight be within the first week of treatment.
`in
`Next, we examined the tmpact of VISTA mAb treatment
`mice bearing melanoma BIGOVA, which expresses the chicken
`ovalbumin as aneo Limorantigen, Despite the apparent immu
`nogenicity and short halllife of 1Sh3 i vive, 13P3 treatment
`signilicamtly suppressed tumor growth in the BL6OVA madel
`(Pig. TA). Increased number of IFN-y-producing cells in’
`the
`tumordraining lymph node was deteeted by ELISPOT assay in
`response Lo irradiated tumor cells, indicating that VISTA mAb
`treatment enhanced tumorspecitic “Tecell
`responses. Even
`though we cannot detect any expression of VISTA on nonhe
`Mmatopoietic cells, we examined in vitro cultured tumor cells to
`exclude the possibility that VISTA mAb directly affeeted tumor
`cell proliferation and apoptosis (Supplementary Vig. $2),
`
`by intradermal injection of LOPE tamoxifen (LO pEL dissolved in
`dimethyl sulfoxide) on the lower back. Cumer vaceine con
`VISTA mAb treatment alters the cellular composition of
`sisted of CD40 agonistic antibody PGk C1O0 pi), LPS (30 pte),
`the tumor immune microenvironment
`polyke C100 ta), CpG (ODN 1826, $0 (ho), Gardiquiniod (40 pie),
`Phe VME plays a crucial role in suppressing tumor-speecilic
`humor antigen peptide PRET CN06-
`150: 100 fie), indo mutated
`-cell responses (25, 26). VISTA is found to be highly expressed
`I
`TRP2 peptide DeltaV PRPS (E80.
`188;
`TOO)
`fies pets, 2-24).
`on tumorinfiltrating myeloid cells,
`inchiding myeloid DCs
`Vaecine mixture was applied with split dose sabeutineoush
`(CDLIb CD Te Gert) and myeloid-derived suppressor cells
`on indicated days. Por prophylactic ate VISTA nib beet
`(CDT Grl CDEC)
`). but
`is not expressed on Blo tumor
`ment, mice were treated every 2 clays with S