HIGHLIGHTS FROM THE LITERATURE

249 What We're Reading

CANCER IMMUNOLOGY AT THECROSSROADS

250 Designing Late-Stage Randomized ClinicalTrials with Cancer Immunotherapy: Can We MakeIt Simpler?Tai-Tsang Chen

RESEARCH ARTICLES

255 YAP-Induced PD-L1 Expression Drives ImmuneEvasion in BRAFi-Resistant MelanomaMin Hwan Kim, Chang Gon Kim, Sang-Kyum Kim,Sang Joon Shin, Eun Ah Choe, Su-Hyung Park,Eui-Cheol Shin, and Joon KimTranscription factor YAP increases PD-L1 expression in BRAFinhibitor-resistant melanoma cells, promoting their direct evasionof T-cell killing. Inhibition of this YAP-orchestrated interplaybetween inhibitor resistance and immune evasion could improvethe treatment of BRAF-mutant melanoma patients.

267 CCL20 Expression by Tumor-AssociatedMacrophages Predicts Progression of HumanPrimary Cutaneous MelanomaRafael Samaniego, Alejandra Guti�errez-Gonz�alez,Alba Guti�errez-Seijo, Sandra S�anchez-Gregorio,Jorge Garcí�a-Gim�enez, Enrique Mercader,Iv�an M�arquez-Rodas, Jos�e Antonio Avil�es, Miguel Relloso,and Paloma S�anchez-MateosMelanoma tumor cells interact synergistically with pro-metastaticmacrophages through a CCR6/CCL20 paracrine signaling loop.Stromal expression of CCL20 in primary melanomas may be auseful tool for assessing patient risk, making treatment decisions,and planning clinical trials.

276 Tumor Immunity and Survival as a Function ofAlternative Neopeptides in Human CancerAndrew J. Rech, David Balli, Alejandro Mantero,Hemant Ishwaran, Katherine L. Nathanson, Ben Z. Stanger,and Robert H. VonderheideAnalysis of neopeptides across multiple tumor types revealed that“alternatively defined neopeptides,” derived from tumor-associated mutations, exhibited higher peptide affinity for MHCcompared with nonmutant counterparts. These neopeptides werestrong predictors of immune phenotype and patient survival.

288 Treatment-Related Adverse Events PredictImproved Clinical Outcome in NSCLC Patients onKEYNOTE-001 at a Single CenterAaron Lisberg, D. Andrew Tucker, Jonathan W. Goldman,Brian Wolf, James Carroll, Ariana Hardy, Karolyn Morris,Paulina Linares, Carlos Adame, Marshall L. Spiegel,Courtney Wells, Jordan McKenzie, Blanca Ledezma,Melody Mendenhall, Phillip Abarca, Krikor Bornazyan,Jaime Hunt, Nima Moghadam, Natalie Chong,Danielle Nameth, Caitlin Marx, John Madrigal,Sitaram Vangala, Narek Shaverdian, David Elashoff, andEdward B. GaronA retrospective analysis of non–small cell lung carcinoma patientstreated with pembrolizumab found that treatment-related adverseevents predicted improved clinical outcome. This observation couldidentify the patients most likely to benefit from anti–PD-1therapy.

295 Prognostic Significance of PD-L1þ and CD8þ

Immune Cells in HPVþ Oropharyngeal SquamousCell CarcinomaBenjamin Solomon, Richard J. Young, Mathias Bressel,Damien Urban, Shona Hendry, Alesha Thai,Christopher Angel, Afaf Haddad, Marcin Kowanetz,Tsien Fua, June Corry, Stephen Fox, and Danny RischinAssessment of CD8þ cell infiltration and PD-L1 expressionon intratumoral immune cells identified a subgroup ofHPVþ OPSCC patients with excellent clinical outcomes.Immunophenotyping tumors provided prognostic informationbeyond that provided by existing TNM-based stagingsystems.

305 Integration of Oncogenes via Sleeping Beauty as aMouse Model of HPV16þ Oral Tumors andImmunologic ControlYi-Hsin Lin, Ming-Chieh Yang, Ssu-Hsueh Tseng,Rosie Jiang, Andrew Yang, Emily Farmer, Shiwen Peng,Talia Henkle, Yung-Nien Chang, Chien-Fu Hung, andT.-C. WuA preclinical mouse model of spontaneous, HPVþ oral tumors wasgenerated. Sleeping beauty transposase system-mediatedoncogene transfection was assisted by electroporation. This modelallowed for the evaluation of disease intervention efficacy andanalysis of tumor cell migration.

March 2018 � Volume 6 � Issue 3

Cancer Immunology Research

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320 Combination Gemcitabine and WT1 PeptideVaccination Improves Progression-Free Survivalin Advanced Pancreatic Ductal Adenocarcinoma:A Phase II Randomized StudySumiyuki Nishida, Takeshi Ishikawa, Shinichi Egawa,Shigeo Koido, Hiroaki Yanagimoto, Jun Ishii,Yoshihide Kanno, Satoshi Kokura, Hiroaki Yasuda,Mari Saito Oba, Maho Sato, Soyoko Morimoto,Fumihiro Fujiki, Hidetoshi Eguchi, Hiroaki Nagano,Atsushi Kumanogoh, Michiaki Unno, Masanori Kon,Hideaki Shimada, Kei Ito, Sadamu Homma,Yoshihiro Oka, Satoshi Morita, and Haruo SugiyamaPancreatic ductal adenocarcinoma patients were treated withgemcitabine and a WT1 peptide vaccine in a multi-institutionalstudy. The combination proved synergistic, prolongingprogression-free survival that was associated with WT1-specificimmune responses. No unexpected toxicities were seen.

332 Mast Cell–Dependent CD8þ T-cell RecruitmentMediates Immune Surveillance of IntestinalTumors in ApcMin/þ MiceSobha R. Bodduluri, StevenMathis, ParamahamsaMaturu,Elangovan Krishnan, Shuchismita R. Satpathy,Paula M. Chilton, Thomas C. Mitchell, Sergio Lira,Massimo Locati, Alberto Mantovani,Venkatakrishna R. Jala, and Bodduluri HaribabuMast cells, depending on the microenvironment, can promote orsuppress tumor progression. Chemokine-mediated recruitment ofmast cells was an essential prerequisite for the initiation of LTB4/BLT1-regulated CD8þ T-cell homing and generation ofantitumor immunity against intestinal tumors.

348 NK Cells Control Tumor-Promoting Function ofNeutrophils in MiceKeisuke Ogura, Marimo Sato-Matsushita, Seiji Yamamoto,Takashi Hori, Masakiyo Sasahara, Yoichiro Iwakura,Ikuo Saiki, Hideaki Tahara, and Yoshihiro HayakawaNK cells control the tumor-promoting function of neutrophils viaan IFNg-mediated mechanism. In mice lacking NK cells,neutrophils promoted tumor growth and angiogenesis. In micelacking both NK cells and the IL17A-neutrophil axis, tumorprogression was reduced.

358 The Antigen ASB4 on Cancer Stem Cells Serves asa Target for CTL Immunotherapy of ColorectalCancerSho Miyamoto, Vitaly Kochin, Takayuki Kanaseki,Ayumi Hongo, Serina Tokita, Yasuhiro Kikuchi,Akari Takaya, Yoshihiko Hirohashi, Tomohide Tsukahara,Takeshi Terui, Kunihiko Ishitani, Fumitake Hata,Ichiro Takemasa, Akihiro Miyazaki, Hiroyoshi Hiratsuka,Noriyuki Sato, and Toshihiko TorigoeTheASB4antigen elicitedCTL responses specific to cancer stem cells(CSCs). Adoptive CTL therapy showed that CSCs are the minimaland necessary target to control colorectal cancer and provide arationale for targeting CSCs as a recurrence-prevention strategy.

CORRECTION

370 Correction: CAR-T Cells Inflict SequentialKilling of Multiple Tumor Target Cells

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ABOUT THE COVER

Patients respond better to immunotherapy if theirtumors have generated abundant neopeptides.However, not all identified neopeptides areimmunogenic, even after selection based onalgorithms predicting affinity for class I or class IImajor histocompatibility antigens. By comparingthe neopeptides from more than 6,300 patientswith 27 types of tumors, Rech and colleaguesidentified alternatively defined neopeptides bytheir ability to bind to MHC at least 10 timesbetter than their normal unmutated counterparts.These ''ADNs'' provide a rich, unexplored pool ofpossible antigenic targets for immunotherapy.Read more starting on page 276 of this issue. Theoriginal image of a Masson's trichrome stainedpancreatic tumor was provided by Dr. Emma E.Furth, Professor of Pathology and LaboratoryMedicine, Head of Gastrointestinal Pathology,Hospital of the University of Pennsylvania.Connective tissue, blue; cells, magenta. Artworkby Lewis Long.

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