WHAT WE'RE READING

347 A Sampling of Highlights from the Literature

CANCER IMMUNOLOGY AT THECROSSROADS

348 Antibody–Cytokine Fusions: Versatile Products forthe Modulation of Anticancer ImmunityDario Neri

PRIORITY BRIEF

355 TIGIT and PD-1 Mark Intratumoral T Cells withReduced Effector Function in B-cell Non-HodgkinLymphomaSarah E. Josefsson, Klaus Beiske, Yngvild N. Blaker,Mette S. Førsund,HaraldHolte, BjørnØstenstad, Eva Kimby,Hakan K€oksal, S�ebastien W€alchli, Baoyan Bai,ErlendB. Smeland, Ronald Levy, Arne Kolstad, KanutteHuse,and June H. MyklebustExpression of TIGIT and PD-1 correlates with impaired T-celleffector function in intratumoral T cells. TIGIT and PD-1 ligandsare expressed in the tumor microenvironment. Combinatorialblockade of TIGIT and PD-1 may be a useful therapy in NHL.

RESEARCH ARTICLES

363 NK Cells Expressing a Chimeric ActivatingReceptor Eliminate MDSCs and Rescue ImpairedCAR-T Cell Activity against Solid TumorsRobin Parihar, Charlotte Rivas, Mai Huynh, Bilal Omer,Natalia Lapteva, Leonid S. Metelitsa, StephenM. Gottschalk,and Cliona M. RooneyInfusion of NK cells that target myeloid-derived suppressor cellsof the solid tumor microenvironment can reduceimmunosuppression and recruit and activate antitumor T cells,resulting in enhanced efficacy and durable responses fortreatment of patients with solid tumors.

376 CCR2-Dependent Recruitment of Tregs andMonocytes Following Radiotherapy Is Associatedwith TNFa-Mediated ResistanceMichele Mondini, Pierre-Louis Loyher, Pauline Hamon,Marine Gerb�e de Thor�e, Marie Laviron, Kevin Berthelot,C�eline Cl�emenson, Benoit L. Salomon,Christophe Combadi�ere, Eric Deutsch, andAlexandre BoissonnasLocal radiation therapy of head and neck squamous cell carcinomatumors induces distinct CCR2-dependent waves of Treg andTNFa-producing monocyte infiltration. TNFa inhibition limitsTreg functions and improves radiotherapy efficacy, paving theway for combined radioimmunotherapies.

388 Activated Eosinophils Exert AntitumorigenicActivities in Colorectal CancerHadar Reichman, Michal Itan, Perri Rozenberg,Tal Yarmolovski, Eli Brazowski, Chen Varol, Nathan Gluck,Shiran Shapira, Nadir Arber, Udi Qimron,Danielle Karo-Atar, James J. Lee, and Ariel MunitzEosinophils, known from the context of allergic inflammation, arealso found in various solid tumors including colorectal cancer. Theanticancer activities of eosinophils in colorectal cancer arecharacterized here.

401 Host Immunity Following Near-InfraredPhotoimmunotherapy Is Enhanced with PD-1Checkpoint Blockade to Eradicate EstablishedAntigenic TumorsTadanobu Nagaya, Jay Friedman, Yasuhiro Maruoka,Fusa Ogata, Shuhei Okuyama, Paul E. Clavijo,Peter L. Choyke, Clint Allen, and Hisataka KobayashiPD-1 blockade reverses adaptive immune resistancefollowing near-infrared photoimmunotherapy to enhancepolyclonal T-cell responses, causing rejection of establishedsyngeneic tumors in both treated and distant untreated tumors.These responses also enhanced immunologic memory developmentthat suppressed recurrence.

414 SUV39H1 Represses the Expression of CytotoxicT-Lymphocyte Effector Genes to Promote ColonTumor Immune EvasionChunwan Lu, Dafeng Yang, John D. Klement, II Kyu Oh,Natasha M. Savage, Jennifer L. Waller, Aaron H. Colby,Mark W. Grinstaff, Nicholas H. Oberlies, Cedric J. Pearce,Zhiliang Xie, Samuel K. Kulp, Christopher C. Coss,Mitch A. Phelps, Thomas Albers, Iryna O. Lebedyeva, andKebin LiuSUV39H1, a H3K9me3-specific histone methyltransferase, wasevaluated in the tumor microenvironment of human and mousecolorectal cancer tumors. CTL effector gene expression wasrepressed by SUV39H1, leading to impaired CTL function thatallowed for tumor immune escape.

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March 2019 � Volume 7 � Issue 3

Cancer Immunology Research

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428 A CD40 Agonist and PD-1 Antagonist AntibodyReprogram the Microenvironment ofNonimmunogenic Tumors to AllowT-cell–Mediated Anticancer ActivityHayley S. Ma, Bibhav Poudel, Evanthia Roussos Torres,John-William Sidhom, Tara M. Robinson,Brian Christmas, Blake Scott, Kayla Cruz, Skylar Woolman,Valerie Z. Wall, Todd Armstrong, and Elizabeth M. JaffeeReprogramming of the tumor microenvironment fromimmune resistance to responsiveness was achieved by triplecombination therapy with a T cell–inducing vaccine, CD40agonist, and PD-1 antagonist in mouse models of breastand metastatic pancreatic cancers.

443 IL2/Anti-IL2 Complex Combined with CTLA-4,But Not PD-1, Blockade Rescues Antitumor NKCell Function by Regulatory T-cell ModulationPamela Caudana, Nicolas Gonzalo Núñez,Philippe De La Rochere, Anaïs Pinto, Jordan Denizeau,Ruby Alonso, Leticia Laura Niborski, Olivier Lantz,Christine Sedlik, and Eliane PiaggioCombination of IL2/anti-IL2 complexes (IL2Cx) with PD-1 orCTLA-4 pathway blockade controls tumor growth and actsdifferentially on CD8þ, NK cells, and Treg cells. Only theIL2Cx/anti–CTLA-4 combination is dependent upon NK cells.

458 Association of Tumor Microenvironment T-cellRepertoire and Mutational Load with ClinicalOutcome after Sequential CheckpointBlockade in MelanomaErik Yusko, Marissa Vignali, Richard K. Wilson,Elaine R. Mardis, F. Stephen Hodi, Christine Horak,Han Chang, David M. Woods, Harlan Robins, andJeffrey WeberOrder matters. Clinical outcomes were associated with themutational and neoantigen loads, and T-cell infiltrates, ofpretreatment samples in a checkpoint blockade phase II trial onlyif nivolumab is used before ipilimumab, but not the reversesequence.

466 Rapamycin Prevents Surgery-Induced ImmuneDysfunction in Patients with Bladder CancerRobert S. Svatek, Niannian Ji, Essel de Leon,Neelam Z. Mukherjee, Aashish Kabra, Vincent Hurez,Marlo Nicolas, Joel E. Michalek, Martin Javors,Karen Wheeler, Z. Dave Sharp, Carolina B. Livi,Zhen-Ju Shu, David Henkes, and Tyler J. CurielData from patients and a mouse model show that surgery forbladder cancer causes immune dysfunction and decreasesefficacy of immunotherapy. Low-dose rapamycin mitigated theseproblems through effects on the tumor and through modulatingT-cell function.

476 Endoplasmic Reticulum Stress Contributes toMitochondrial Exhaustion of CD8þ T CellsKatie E. Hurst, Kiley A. Lawrence, Matthew T. Essman,Zeke J. Walton, Lee R. Leddy, and Jessica E. ThaxtonThe PERK-mediated chronic stress axis contributes to themitochondrial exhaustion that PD-1þCD8þ tumor-infiltratingT cells undergo. Targeting the PERK axis augments T-cellefficacy in tumors and aids anti-PD-1 therapy.

487 LIN28/let-7/PD-L1 Pathway as a Target for CancerImmunotherapyYanlian Chen, Chen Xie, Xiaohui Zheng, Xin Nie,Zining Wang, Haiying Liu, and Yong ZhaoPD-L1 expression in cancers is regulated through the LIN28/let-7 pathway and manipulated using the small compoundLIN28-inhibitor C1632. Treatment with this compoundincreases antitumor immunity and inhibits tumor cell growthin vitro and in a mouse breast cancer model.

498 GM-CSF Promotes Antitumor Immunity byInducing Th9 Cell ResponsesIl-Kyu Kim, Choong-Hyun Koh, Insu Jeon,Kwang-Soo Shin, Tae-Seung Kang, Eun-Ah Bae,Hyungseok Seo, Hyun-Ja Ko, Byung-Seok Kim,Yeonseok Chung, and Chang-Yuil KangGranulocyte-macrophage colony-stimulating factor (GM-CSF)functions as an adjuvant for antitumor immunity through anunclear mechanism. By activating monocyte-derived dendriticcells, GM-CSF induces Th9 development and IL9 production,which facilitates antitumor cytotoxic T lymphocyte responses.

510 Immune-Checkpoint Blockade Opposes CD8þ

T-cell Suppression in Human and MurineCancerLukas W. Pfannenstiel, C. Marcela Diaz-Montero,Ye F. Tian, Joseph Scharpf, Jennifer S. Ko, andBrian R. GastmanIn this study of squamous cell carcinoma of the head andneck, checkpoint blockade therapy prevents development ofsuppressive CD8þ T cells that would otherwise dampenantitumor immune responses.

CORRECTION

526 Correction: Phage-Based Anti-HER2 VaccinationCan Circumvent Immune Tolerance againstBreast Cancer

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ABOUT THE COVER

Cytotoxic T lymphocytes (CTLs) play a keyrole in antitumor immunity, and the functionof these cells can be suppressed in the tumormicroenvironment (TME). Lu et al. show howepigenetic states in the TME suppress effectorfunctions and can be countered by smallmolecule–targeted therapy in colon cancer.CTLs infiltrate tumors and have highexpression of the histone methyltransferaseSUV39H1, which decorates the histoneH3K9me3. H3K9me3 is enriched in thepromoter region of several key CTL effectorgenes and suppressed their expression. Byspecifically targeting SUV39H1 with a small-molecule inhibitor, called F5446, expressionof the effector genes is enhanced, and theantitumor function of CTLs in the tumormicroenvironment is increased. Read more inthis issue on page 414. Original image fromFig. 1. Artwork by Lewis Long.

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2019;7:347-526. Cancer Immunol Res     7 (3)

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