WHAT WE'RE READING

853 A Sampling of Highlights from the Literature

CANCER IMMUNOLOGY AT THECROSSROADS

854 Pulling RANK on Cancer: Blocking Aire-MediatedCentral Tolerance to Enhance ImmunotherapyMaureen A. Su and Mark S. Anderson

CANCER IMMUNOLOGY MINIATURES

860 IL17A Blockade Successfully Treated PsoriasiformDermatologic Toxicity from ImmunotherapyDaniel Johnson,AnishaB.Patel,Marc I.Uemura,VanA. Trinh,Natalie Jackson, Chrystia M. Zobniw, Michael T. Tetzlaff,Patrick Hwu, Jonathan L. Curry, and Adi DiabPatients with skin lesions as a result of immune checkpoint inhibitortherapy are usually treated with corticosteroids. A patient with severepsoriasiform dermatologic toxicity was treated with anti-IL17Ainstead, which cleared the skin without altering response topembrolizumab.

866 Phenotypic and Genomic Determinants ofImmunotherapy Response Associated withSquamousnessAaron M. Goodman, Shumei Kato,Ranajoy Chattopadhyay, Ryosuke Okamura,Ila M. Saunders, Meagan Montesion, Garrett M. Frampton,Vincent A. Miller, Gregory A. Daniels, and Razelle KurzrockTumor mutational burden (TMB) differs between squamous cellcarcinomas (SCCs) and non-SCCs. Amongst SCC subtypes,cutaneous disease has the highest TMB, and both high TMB andcutaneous histology correlate with better outcome in patients afterimmune checkpoint blockade.

RESEARCH ARTICLES

874 IL1R8 Deficiency Drives Autoimmunity-AssociatedLymphoma DevelopmentFederica Riva, Maurilio Ponzoni, Domenico Supino,Maria Teresa Sabrina Bertilaccio, Nadia Polentarutti,Matteo Massara, Fabio Pasqualini, Roberta Carriero,Anna Innocenzi, Achille Anselmo, Tania Veliz-Rodriguez,Giorgia Simonetti, Hans-Joachim Anders,Federico Caligaris-Cappio, Alberto Mantovani,Marta Muzio, and Cecilia GarlandaSilencing of the regulatory receptor IL1R8 in mice is associatedwith increased lymphoproliferation in autoimmunity-associatedB-cell lymphoma. IL1R8 expression correlates with survival inhuman diffuse large B-cell lymphoma, suggesting that targetingIL1R8 may present an avenue for future therapies.

886 Programmed Cell Death Ligand-1 (PD-L1) andCD8 Expression Profiling Identify an ImmunologicSubtype of Pancreatic Ductal Adenocarcinomaswith Favorable SurvivalLudmila Danilova, Won Jin Ho, Qingfeng Zhu,Teena Vithayathil, Ana De Jesus-Acosta, Nilofer S. Azad,Daniel A. Laheru, Elana J. Fertig, Robert Anders,Elizabeth M. Jaffee, and Mark YarchoanTwo independent cohorts of patients with pancreatic ductaladenocarcinoma (PDAC) were evaluated and a subset of patientswith favorable prognosis was identified. These results highlightthat in PDAC, the antitumor response is a feature of long-termsurvival.

896 Function of Human Tumor-InfiltratingLymphocytes in Early-Stage Non–Small Cell LungCancerShaun M. O'Brien, Astero Klampatsa, Jeffrey C. Thompson,Marina C. Martinez, Wei-Ting Hwang, Abishek S. Rao,Jason E. Standalick, Soyeon Kim, Edward Cantu,Leslie A. Litzky, Sunil Singhal, Evgeniy B. Eruslanov,Edmund K. Moon, and Steven M. AlbeldaCD103þ tissue-resident memory (TRM) T cells are key forantitumor activity in non-small cell lung cancer and are negativelyinfluenced by eomesoderin (Eomes). TIL function may be drivenby competition between an antitumor TRM program and anEomes-associated exhaustion program.

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June 2019 � Volume 7 � Issue 6

Cancer Immunology Research

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910 Endogenous CD4þ T Cells Recognize Neoantigensin Lung Cancer Patients, Including RecurrentOncogenic KRAS and ERBB2 (Her2) DriverMutationsJoshua R. Veatch, Brenda L. Jesernig, Julia Kargl,Matthew Fitzgibbon, Sylvia M. Lee, Christina Baik,Renato Martins, A. McGarry Houghton, andStanley R. RiddellIt is demonstrated that patients with non-small cell lung cancercommonly have CD4þ T-cell responses to neoantigens. These Tcells show reactivity to recurrent driver mutations, identifying apotential role for CD4þ T cells in immunotherapies.

923 The Tumor Immune Microenvironment Drives aPrognostic Relevance That Correlates withBladder Cancer SubtypesCarolin Pfannstiel; Pamela L. Strissel; on behalf of theBRIDGEConsortium, Germany, Katherine B. Chiappinelli;Danijel Sikic, Sven Wach, Ralph M. Wirtz; on behalf of theBRIDGE Consortium, Germany, Adrian Wullweber; HelgeTaubert, Johannes Breyer, Wolfgang Otto, Thomas Worst,Maximilian Burger, Bernd Wullich, Christian Bolenz; onbehalf of the BRIDGE Consortium, Germany, NicoleFuhrich, Carol I. Geppert; Veronika Weyerer, RobertStoehr, Simone Bertz, Bastian Keck, Franziska Erlmeier,Philipp Erben, Arndt Hartmann, Reiner Strick, and MarkusEckstein; on behalf of the BRIDGE Consortium, GermanyAnalysis of 542 patients with muscle-invasive bladder cancershows that spatial organization of immune cells with specificphenotypes correlates with tumor mutational burden and tumorsubtypes. These data could predict favorable outcome followingcystectomy and adjuvant chemotherapy.

939 CD28 Homolog Is a Strong Activator of NaturalKiller Cells for Lysis of B7H7þ Tumor CellsXiaoxuan Zhuang and Eric O. LongNK cells express CD28H, a CD28 homolog, which enhancescytotoxicity against tumor cells expressing its ligand B7H7.Expression of a CD28H chimeric antigen receptor overridesinhibition by HLA class I receptors and shows promise asimmunotherapy.

952 NKT Cell–Driven Enhancement of AntitumorImmunity Induced by Clec9a-Targeted TailorableNanoemulsionPui Yeng Lam, Takumi Kobayashi, Megan Soon,Bijun Zeng, Riccardo Dolcetti, Graham Leggatt,Ranjeny Thomas, and Stephen R. MattarolloAntigen and a-galactosylceramide encapsulated in ananoemulsion improved the function of iNKT and dendriticcells, which drove cross-priming of antigen-specific CD8þ T cells.Long-term control of solid tumors resulted from a single dose ofthe emulsion.

963 Coexpression of Inhibitory Receptors Enriches forActivated and Functional CD8þ T Cells in MurineSyngeneic Tumor ModelsHuizhong Xiong, Stephanie Mittman, Ryan Rodriguez,Patricia Pacheco-Sanchez, Marina Moskalenko,Yagai Yang, Justin Elstrott, Alex T. Ritter, S€oren M€uller,Dorothee Nickles, Teresita L. Arenzana,Aude-H�el�ene Capietto, L�elia Delamarre, Zora Modrusan,Sascha Rutz, Ira Mellman, and Rafael CubasInhibitory receptor coexpression is thought to serve as a proxy forexhausted T cells, but can define activated T cells responsive tocheckpoint blockade. Cells coexpressing inhibitory receptors maythus be responsive to treatment in the clinic.

977 Differential Effects of Depleting versusProgramming Tumor-Associated Macrophages onEngineered T Cells in Pancreatic DuctalAdenocarcinomaIngunn M. Stromnes, Adam L. Burrack, Ayaka Hulbert,Patrick Bonson, Cheryl Black, J. Scott Brockenbrough,Jackson F. Raynor, Ellen J. Spartz, Robert H. Pierce,Philip D. Greenberg, and Sunil R. HingoraniCsf1R blockade in a model of pancreatic ductal adenocarcinomanegatively impacted the function of infused engineered T cells.Addition of a CD40 agonist increased the persistence of theinfused T cells but ultimately, did not rescue their function.

990 Farnesoid X Receptor Constructs anImmunosuppressive Microenvironment andSensitizes FXRhighPD-L1low NSCLC to Anti–PD-1ImmunotherapyWenjie You, Lijun Li, Deqiao Sun, Xueqing Liu,Zongjun Xia, Shan Xue, Bi Chen, Hui Qin, Jing Ai, andHandong JiangA subtype of non-small cell lung cancer is characterized byimmunosuppression through the farnesoid X receptor (FXR) andresponsiveness to anti–PD-1 therapy. The combination of highFXR expression and low PD-L1 expression may identify patientsreceptive to anti–PD-1 immunotherapy.

1001 Tumor-Derived a-Fetoprotein Suppresses FattyAcid Metabolism and Oxidative Phosphorylationin Dendritic CellsPatricia M. Santos, Ashley V. Menk, Jian Shi, Allan Tsung,Greg M. Delgoffe, and Lisa H. ButterfieldAFP secreted by hepatocellular cancer cells inhibits fatty acidsynthesis and oxidative phosphorylation in dendritic cells. Theseeffects on mitochondrial metabolism are mediated throughmTORC1, SREBP-1, and PGC1a, resulting inimmunosuppression.

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1013 MicroRNA-155 Expression Is Enhanced by T-cellReceptor Stimulation Strength and Correlates withImproved Tumor Control in MelanomaAmaia Martinez-Usatorre, Lorenzo F. Sempere,Santiago J. Carmona, Laura Carretero-Iglesia,Gwenna€elle Monnot, Daniel E. Speiser, Nathalie Rufer,Alena Donda, Dietmar Zehn, Camilla Jandus, andPedro RomeroT-cell receptor stimulation strength dictates microRNA-155expression in CD8þ T cells. High miR-155 levels anddownregulation of its targets correlate with tumor control inmelanoma, suggesting their utility as a CD8þ T-cellresponsiveness biomarker.

1025 Poor Response to Neoadjuvant ChemotherapyCorrelates with Mast Cell Infiltration inInflammatory Breast CancerSangeetha M. Reddy, Alexandre Reuben, Souptik Barua,Hong Jiang, Shaojun Zhang, Linghua Wang,Vancheswaran Gopalakrishnan, Courtney W. Hudgens,Michael T. Tetzlaff, James M. Reuben, Takahiro Tsujikawa,Lisa M. Coussens, Khalida Wani, Yan He, Lily Villareal,Anita Wood, Arvind Rao, Wendy A. Woodward,Naoto T. Ueno, Savitri Krishnamurthy, Jennifer A. Wargo,and Elizabeth A. MittendorfMast cell infiltration and density correlate with poor clinicaloutcomes and responses to therapy in patients with inflammatorybreast cancer. These cells may be contributing to animmunosuppressive microenvironment and could be targeted toimprove therapeutic responses.

ABOUT THE COVER

Development of B-cell lymphoma isassociated with chronic inflammation, andautoimmune disease can be a driver of suchinflammation. The inhibitory IL1R familymember, IL1R8, modulates inflammatoryresponses. Riva et al. show that a deficiency ofIL1R8 in autoimmune-prone mice, that leadsto exacerbated autoimmune disease andinflammation, results in B-celltransformation and the development ofdiffuse large B-cell lymphoma (DLBCL).IL1R8 inhibits MyD88–NF-kB activation, andthus, IL1R8 deficiency led to constitutivesignaling of this pathway in splenic B cells,resulting in their uncontrolled expansion. Inhuman DLBCL, IL1R8 expression isdownregulated. Higher IL1R8 expression isassociated with better outcomes in patientswith DLBCL. This study highlights theintersection of cancer and autoimmunity andillustrates how inflammation caused byIL1R8 deficiency can drive the malignanttransformation of B cells. Read more in thisissue on page 874. Original image fromFig. 3C. Artwork by Lewis Long.

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