Cancer Immunology Research Table of ContentsMetsada Pasmanik-Chor, Lea Ziporen, Tamar Geiger, Noam Shomron, and Zvi Fishelson Cancer cells respond poorly to antibody-based immunotherapy

WHAT WE'RE READING

1901 A Sampling of Highlights from the Literature

IN THE SPOTLIGHT

1902 Location-Dependent B-cell Function inGlioblastomaFerdinando PucciSee related article, p. 1928.

PRIORITY BRIEF

1903 Phase II Trial of Ipilimumab with StereotacticRadiation Therapy for Metastatic Disease:Outcomes, Toxicities, and Low-Dose Radiation–Related Abscopal ResponsesJames W. Welsh, Chad Tang, Patricia de Groot, Aung Naing,Kenneth R. Hess, John V. Heymach,Vassiliki A. Papadimitrakopoulou, Taylor R. Cushman,Vivek Subbiah, Joe Y. Chang, George R. Simon,Rishab Ramapriyan, Hampartsoum B. Barsoumian,Hari Menon, Maria Angelica Cortez, Erminia Massarelli,Quynh Nguyen, Padmanee Sharma, James P. Allison,Adi Diab, Vivek Verma, Uma Raju, Sherif G. Shaaban,Ramona Dadu, Maria E. Cabanillas, Kelvin Wang,Clark Anderson, Daniel R. Gomez, Stephen Hahn,Ritsuko Komaki, and David S. HongDetermining combination therapies to improve immunecheckpoint blockade can benefit patient outcome. In a phase IIclinical trial, ipilimumab plus stereotactic radiotherapy providesclinical benefit to metastatic cancer patients.

RESEARCH ARTICLES

1910 Tumor Vessel Normalization, ImmunostimulatoryReprogramming, and Improved Survival inGlioblastoma with Combined Inhibition of PD-1,Angiopoietin-2, and VEGFMariangela Di Tacchio, Jadranka Macas,Jakob Weissenberger, Kathleen Sommer, Oliver B€ahr,Joachim P. Steinbach, Christian Senft, Volker Seifert,Martin Glas, Ulrich Herrlinger, Dietmar Krex,Matthias Meinhardt, Astrid Weyerbrock, Marco Timmer,Roland Goldbrunner, Martina Deckert, Andreas H. Scheel,Reinhard B€uttner, Oliver M. Grauer, Jens Schittenhelm,Ghazaleh Tabatabai, Patrick N. Harter, Stefan G€unther,Kavi Devraj, Karl H. Plate, and Yvonne ReissThe combination of anti–PD-1 and anti-VEGF/Ang-2 therapyshows efficacy in glioblastoma, a cancer considered to be non-Tcell–inflamed. These data highlight how immune therapy efficacycan be improved by also targeting angiogenic factors in this cancer.

1928 Myeloid-Derived Suppressive Cells Promote Bcell–Mediated Immunosuppression via Transfer ofPD-L1 in GlioblastomaCatalina Lee-Chang, Aida Rashidi, JasonMiska, Peng Zhang,Katarzyna C. Pituch, David Hou, Ting Xiao,Mariafausta Fischietti, Seong Jae Kang, Christina L. Appin,Craig Horbinski, Leonidas C. Platanias, Aurora Lopez-Rosas,Yu Han, Irina V. Balyasnikova, and Maciej S. LesniakRegulatory B cells (Bregs) can regulate the activation and functionof CD8þ T cells in glioblastoma. MDSCs were found to promoteBreg differentiation and suppressive function via transfer ofPD-L1–bound microvesicles taken up by infiltrating B cells.See related Spotlight, p. 1902.

1944 IL6 Modulates the Immune Status of the TumorMicroenvironment to Facilitate MetastaticColonization of Colorectal Cancer CellsYujiro Toyoshima, Hidemitsu Kitamura, Huihui Xiang,Yosuke Ohno, Shigenori Homma, Hideki Kawamura,Norihiko Takahashi, Toshiya Kamiyama, Mishie Tanino,and Akinobu TaketomiIL6 deficiency reduces colorectal cancer metastasis to the liverand augments the effector functions of CD8þ T cells. Datahighlight that IL6 blockade may be a potential strategy forimproving antitumor immunity in colorectal cancer.

1958 Trifluridine/Tipiracil plus Oxaliplatin ImprovesPD-1 Blockade in Colorectal Cancer by InducingImmunogenic Cell Death and DepletingMacrophagesEmeric Limagne, Marion Thibaudin, Lisa Nuttin,Aodrenn Spill, Valentin Derang�ere, Jean-David Fumet,Nadia Amellal, Elisa Peranzoni, Val�erie Cattan, andFrancois GhiringhelliThe induction of immunogenic cell death (ICD) in tumorsenhances immune checkpoint blockade. Trifluridine/tipiracilplus oxaliplatin induces T cell–dependent ICD in murine coloncancer and depletes immunosuppressive macrophages.

1970 MicroRNAs Affect Complement RegulatorExpression and Mitochondrial Activity to ModulateCell Resistance to Complement-DependentCytotoxicityYaron Hillman, Mariya Mardamshina,Metsada Pasmanik-Chor, Lea Ziporen, Tamar Geiger,Noam Shomron, and Zvi FishelsonCancer cells respond poorly to antibody-based immunotherapy dueto their enhanced resistance to activated complement. MicroRNAswere found to regulate complement resistance in multiple tumorcells, and thus, targeting them may potentiate the success ofantibody-based cancer therapy.

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December 2019 � Volume 7 � Issue 12

Cancer Immunology Research

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1984 ALK and RET Inhibitors Promote HLA Class IAntigen Presentation and Unmask New Antigenswithin the Tumor ImmunopeptidomeClaire Y. Oh,Martin G. Klatt, Christopher Bourne, Tao Dao,Megan M. Dacek, Elliott J. Brea, Sung Soo Mun,Aaron Y. Chang, Tatyana Korontsvit, andDavid A. ScheinbergIncreasing HLA expression in the tumor microenvironment couldimprove T cell–based immune therapies. ALK and RET inhibitionin the appropriate kinase mutant tumors impedes MAPKsignaling, leading to an increase in HLA expression and alteredepitope presentation.

1998 Tumor-Specific Regulatory T Cells from the BoneMarrow Orchestrate Antitumor Immunity inBreast CancerYingzi Ge, Hans-Henning B€ohm, Anchana Rathinasamy,Maria Xydia, Xiaoying Hu, Mudita Pincha,Ludmila Umansky, Christopher Breyer, Michael Hillier,Andreas Bonertz, Alexandra Sevko, Christoph Domschke,Florian Schuetz, Helge Frebel, Steffen Dettling,Christel Herold-Mende, Christoph Reissfelder,J€urgen Weitz, Viktor Umansky, and Philipp BeckhoveMechanisms for how regulatory T cells (Tregs) inhibit antitumorimmune responses are needed to improve therapies. Tumor-specific Tregs from the bone marrow of breast cancer patientsmigrate to the peripheral blood and inhibit antitumor T-cellresponses.

2013 Silencing Fc Domains in T cell–EngagingBispecific Antibodies Improves T-cell Traffickingand Antitumor PotencyLinlin Wang, Sayed Shahabuddin Hoseini, Hong Xu,Vladimir Ponomarev, and Nai-Kong CheungSilencing Fc domains of bispecific antibodies (BsAbs) improvesT-cell trafficking and antitumor effects in GD2þ and HER2þ

tumor systems and two mouse models. Future BsAb designs thatinactivate Fc domains could improve antitumor efficacy and limitorgan toxicities.

2025 T-cell Receptors Engineered De Novo for PeptideSpecificity Can Mediate Optimal T-cell Activitywithout Self Cross-ReactivityPreeti Sharma, Daniel T. Harris, Jennifer D. Stone, andDavid M. KranzCancer antigen–specific TCRs generated by directed evolutionprovide an alternative for adoptive T-cell therapies. A TCRgenerated by molecular evolution showed similar specificity andless cross-reactivity compared to a TCR generated from a T-cellclone.

2036 Trabectedin Reveals a Strategy ofImmunomodulation in Chronic LymphocyticLeukemiaPriyanka Banerjee, Ronghua Zhang, Cristina Ivan,Giovanni Galletti, Karen Clise-Dwyer, Federica Barbaglio,Lydia Scarfò, Miguel Aracil, Christian Klein,William Wierda, William Plunkett,Federico Caligaris-Cappio, Varsha Gandhi,Michael J. Keating, and Maria Teresa S. BertilaccioChronic lymphocytic leukemia is an incurable disease:Intolerance or resistance to current therapies is often generatedby immune cell defects and immunosuppression. Trabectedininhibits leukemia progression and repairs the immune system.

2052 Mammary Tumor Cells with High MetastaticPotential Are Hypersensitive to Macrophage-Derived HGFTakanori Kitamura, Yu Kato, Demi Brownlie,Daniel Y.H. Soong, Ga€el Sugano, Nicolle Kippen,Jiufeng Li, Dahlia Doughty-Shenton, Neil Carragher, andJeffrey W. PollardBreast cancer cells selected for high metastatic potential haveelevated expression of MET and are hyper-responsive tomacrophage-derived HGF, which promotes tumor cellextravasation and outgrowth. Blockade of macrophage-mediatedHGF/MET signaling could have therapeutic potential for breastcancer.

2065 Tumor Immune Microenvironment andChemosensitivity Signature for PredictingResponse to Chemotherapy in Gastric CancerYuming Jiang, Jingjing Xie, Weicai Huang, Hao Chen,Sujuan Xi, Zhen Han, Lei Huang, Tian Lin, Li-Ying Zhao,Yan-Feng Hu, Jiang Yu, Shi-Rong Cai, Tuanjie Li, andGuoxin LiAn SVM (support vector machine) signature, integratingimmune microenvironment and chemosensitivity-relatedimmunohistochemistry features of tumor cells, functions as anindependent prognosis predictor. The signature identifies asubgroup of patients with gastric cancer likely to benefit fromadjuvant chemotherapy.

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ABOUT THE COVER

Glioblastoma is considered to be a non-Tcell–inflamed cancer and has an immunesuppressive tumor microenvironment (TME),creating a hurdle for the efficacy ofimmunotherapy. Glioblastoma also has highexpression of angiogenic factors such as VEGF(vascular endothelial growth factor) andAng-2 (angiopoietin-2). Di Tacchio et al.demonstrate that targeting VEGF and Ang-2in combination with anti–PD-1 canovercome glioblastoma’s suppressive TMEand allows for enhanced antitumor responsesin preclinical models. This triple therapyincreases cytotoxic immune cell infiltrationand reduces myeloid-derived suppressor celland regulatory T-cell numbers. Microvesselassessment of tumors shows that tripletherapy globally normalizes the tumorvasculature, facilitating immune cellinfiltration. These data highlight theimportance of targeting angiogenic factors toimprove the efficacy of immune checkpointtherapy for glioblastoma. Read more in thisissue on page 1910. Original image fromSupplementary Fig. S3A. Artwork byLewis Long.

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2019;7:1901-2073. Cancer Immunol Res     7 (12)

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