WHAT WE'RE READING

527 A Sampling of Highlights from the Literature

CANCER IMMUNOLOGY AT THECROSSROADS

528 Adoptive Immunotherapy with Antigen-SpecificT Cells Expressing a Native TCRWingchi Leung and Helen E. Heslop

CANCER IMMUNOLOGY MINIATURE

534 Immunologic Recognition of a Shared p53Mutated Neoantigen in a Patient with MetastaticColorectal CancerWinifred Lo, Maria Parkhurst, Paul F. Robbins, Eric Tran,Yong-Chen Lu, Li Jia, Jared J. Gartner, Anna Pasetto,Drew Deniger, Parisa Malekzadeh, Thomas E. Shelton,Todd Prickett, Satyajit Ray, Scott Kivitz, Biman C. Paria,Isaac Kriley, David S. Schrump, and Steven A. RosenbergA patient with metastatic colon cancer had T-cell receptorsreactive with a mutation in the tumor suppressor gene TP53. TheTCRs were neoantigen-specific and HLA-A*0201-restricted andcould be used to treat others with tumors sharing the sameparameters.

PRIORITY BRIEFS

544 Early-Life Microbiota Exposure Restricts Myeloid-Derived Suppressor Cell–Driven ColonicTumorigenesisAkihito Harusato, Emilie Viennois, Lucie Etienne-Mesmin,Shingo Matsuyama, Hirohito Abo, Satoru Osuka,Nicholas W. Lukacs, Yuji Naito, Yoshito Itoh, Jian-Dong Li,Didier Merlin, Andrew T. Gewirtz, and Timothy L. DenningMice with altered colon microbiota early in life exhibit augmentedinflammatory cytokine and chemokine expression in the colon.This led to an increased susceptibility to colitis-associated cancerlater in adulthood, demonstrating the microbiota's impact oncolon homeostasis.

552 Broad Cytotoxic Targeting of Acute MyeloidLeukemia by Polyclonal Delta One T CellsBiagio Di Lorenzo, Andr�e E. Sim~oes, Francisco Caiado,Paola Tieppo, Daniel V. Correia, Tania Carvalho,Maria Gomes da Silva, Julie D�echanet-Merville,Ton N. Schumacher, Immo Prinz, Haakan Norell,Sarina Ravens, David Vermijlen, and Bruno Silva-SantosThis study provides preclinical in vitro and in vivo proof-of-concept for use of Delta One T (DOT) cells as immunotherapyto treat acute myeloid leukemia.

RESEARCH ARTICLES

559 CD96 Is an Immune Checkpoint That RegulatesCD8þ T-cell Antitumor FunctionDeepak Mittal, Ailin Lepletier, Jason Madore,Amelia Roman Aguilera, Kimberley Stannard,Stephen J. Blake, Vicki L.J. Whitehall, Cheng Liu,Mark L. Bettington, Kazuyoshi Takeda, Georgina V. Long,Richard A. Scolyer, Ruth Lan, Nathan Siemers,Alan Korman, Michele W.L. Teng, Robert J. Johnston,William C. Dougall, and Mark J. SmythThe antitumor activity of anti-CD96 monotherapy depends onseveral host factors, including CD8þ T cells and immunesignaling. Inhibition of CD96 in combination with other immunecheckpoint inhibitors shows superior antitumor activity over singleor dual agent therapy.

572 Targeted Delivery of IL2 to the Tumor StromaPotentiates the Action of Immune CheckpointInhibitors by Preferential Activation of NK andCD8þ T CellsCornelia Hutmacher, Nicol�as Gonzalo Núñez,Anna Rita Liuzzi, Burkhard Becher, and Dario NeriTreatment of murine tumors with combination checkpointblockade and an antibody-IL2 fusion protein reduces tumorgrowth, an effect dependent on CD8þ T cells and NK cells. Thesedata support the use of engineered IL2 products for anti-cancertherapy.

584 Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance duringChronic Virus InfectionJi Hoon Oh, Myeong Joon Kim, Seong Jin Choi,Young Ho Ban, Heung Kyu Lee, Eui-Cheol Shin,Kyung-Mi Lee, and Sang-Jun HaChronic LCMV infection delays tumor progression as a result ofsustained type I IFN signaling and enhanced NK cell–mediatedimmunosurveillance. This observation could improve thedevelopment of effective treatment strategies for cancer patientswith chronic viral infections.

600 Regulatory T Cells in an Endogenous MouseLymphoma Recognize Specific Antigen Peptidesand Contribute to Immune EscapeFatima Ahmetli�c, Tanja Riedel, Nadine H€omberg,Vera Bauer, Nico Trautwein, Albert Geishauser,Tim Sparwasser, Stefan Stevanovi�c, Martin R€ocken, andRalph MocikatIn a mouse model of B-cell lymphoma, regulatory T cellssuppressed antitumor responses. Treg cells recognized nonmutatedself epitopes, which were characteristic of lymphoma and whichwere related to malignancy.

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Cancer Immunology Research

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609 Automated Analysis of Lymphocytic Infiltration,Tumor Budding, and Their Spatial RelationshipImproves Prognostic Accuracy in ColorectalCancerInes P. Nearchou, Kate Lillard, Christos G. Gavriel,Hideki Ueno, David J. Harrison, and Peter D. CaieAutomated image analysis reveals that high tumor budnumbers, low T-cell density, and few T cells proximal to tumorbuds were associated with reduced survival of CRC patients.This model provided greater prognostic value than currentclinical guidelines.

621 Intravesical Ty21a Vaccine Promotes DendriticCells and T Cell–Mediated Tumor Regression inthe MB49 Bladder Cancer ModelSonia Domingos-Pereira, Karthik Sathiyanadan,Stefano La Rosa, Lenka Pol�ak, Mathieu F. Chevalier,Paul Martel, Rim Hojeij, Laurent Derr�e,Jacques-Antoine Haefliger, Patrice Jichlinski, andDenise Nardelli-HaefligerLow-dose intravesical administration of Ty21a, a commercialtyphoid vaccine, generated effective antitumor DC and T-cellresponses and improved survival in a mouse model of bladdercancer. These results demonstrate the potential of Ty21a forclinical use.

630 Low-Dose Apatinib Optimizes TumorMicroenvironment and Potentiates AntitumorEffect of PD-1/PD-L1 Blockade in Lung CancerSha Zhao, Shengxiang Ren, Tao Jiang, Bo Zhu, Xuefei Li,Chao Zhao, Yijun Jia, Jinpeng Shi, Limin Zhang,Xiaozhen Liu, Meng Qiao, Xiaoxia Chen, Chunxia Su,Hui Yu, Caicun Zhou, Jun Zhang, D. Ross Camidge, andFred R. HirschBoth preclinical and phase IB clinical data indicate that lower-than-conventional doses of the anti-angiogenic agent apatinib(a VEGFR2-TKI) optimized the immunosuppressive tumormicroenvironment and potentiated the therapeutic response toanti-PD-1/PD-L1 immunotherapy in lung cancer.

644 Immune Profiling and Quantitative AnalysisDecipher the Clinical Role of Immune-Checkpoint Expression in the Tumor ImmuneMicroenvironment of DLBCLZiju Y. Xu-Monette, Min Xiao, Qingyan Au,Raghav Padmanabhan, Bing Xu, Nicholas Hoe,Sandra Rodríguez-Perales, Raul Torres-Ruiz,Ganiraju C. Manyam, Carlo Visco, Yi Miao, Xiaohong Tan,Hongwei Zhang, Alexandar Tzankov, Jing Wang,Karen Dybkær, Wayne Tam, Hua You, Govind Bhagat,Eric D. Hsi, Maurilio Ponzoni, Andr�es J.M. Ferreri,Michael B. Møller, Miguel A. Piris, J. Han van Krieken,Jane N. Winter, Jason R. Westin, Lan V. Pham,L. Jeffrey Medeiros, George Z. Rassidakis, Yong Li,Gordon J. Freeman, and Ken H. YoungThe immune profile of the tumor microenvironment in DLBCLpatients was assessed with a MultiOmyx platform. PD-1/L1expression on T cells and PD-L1 expression on macrophages hadprognostic value in identification of patients with poor survivalafter immunochemotherapy.

658 Autologous Lymphocyte Infusion SupportsTumor Antigen Vaccine–Induced Immunity inAutologous Stem Cell Transplant for MultipleMyelomaAdam D. Cohen, Nikoletta Lendvai, Sarah Nataraj,Naoko Imai, Achim A. Jungbluth, Ioanna Tsakos,Adeeb Rahman, Anna Huo-Chang Mei, Herman Singh,Katarzyna Zarychta, Seunghee Kim-Schulze, Andrew Park,Ralph Venhaus, Katherine Alpaugh, Sacha Gnjatic, andHearn J. ChoImmunotherapy can include vaccines in the setting of autologousstem cell transplantation for multiple myeloma. Here, autologouslymphocyte infusion augmented immunotherapy and supportedhumoral and CD4þ helper T-cell immunity in response to atherapeutic tumor vaccine.

670 Radiotherapy and Cisplatin IncreaseImmunotherapy Efficacy by Enabling Local andSystemic Intratumoral T-cell ActivityPaula Kroon, Elselien Frijlink, Victoria Iglesias-Guimarais,Andriy Volkov, Marit M. van Buuren, Ton N. Schumacher,Marcel Verheij, Jannie Borst, and Inge VerbruggeThe response to PD-1 blockade and CD137 agonism could beimproved by ''re-purposing'' radiotherapy or cisplatin tomodulate the tumor microenvironment. Chemo/radio-immunotherapy enhances CTL responses, tumor regression, andsurvival in a mouse model of poorly immunogenic breast cancer.

683 T-cell Activity against AML Improved byDual-Targeted T Cells Stimulated throughT-cell and IL7 ReceptorsEric Krawczyk, Sergey N. Zolov, Kevin Huang, andChallice L. BonifantAn engineered T cell specific for two antigens shows anti-AMLactivity. Combining CD123 recognition and IL7Ractivation enhances antitumor activity and T-cell survivalin preclinical models, suggesting the value of extending thisstrategy to other tumor types.

CORRECTION

693 Correction: Collapse of the PlasmacytoidDendritic Cell Compartment in AdvancedCutaneous Melanomas by Components of theTumor Cell Secretome

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ABOUT THE COVER

CD96 is an immune checkpoint and is knownto suppress T-cell andNK cell effector functions.Thus, CD96 can impair antitumor responses inthe tumor microenvironment. Mittal et al.demonstrate that CD96 blockade can inhibitprimary tumor growth in multiple tumormodels. The effects of anti-CD96 are dependenton several host factors, including CD8þ T cells,cytokines, and DNAM-1/CD226 signaling.Because CD96 is co-expressed with otherimmune checkpoints, especially PD-1, dual andtriple blockade protocols were tested. Dualblockade of CD96 and other immunecheckpoints is more effective than anti-CD96monotherapy, and an optimal triplecombination blocking CD96, PD-1, and TIGITis superior over dual combinations. Thesetreatments increase T-cell infiltration andenhance antitumor responses, highlighting thatcombining the targeting of CD96 with otherimmune checkpoints could be a strategy foraugmenting T-cell responses that suppresstumor growth. Read more in this issue on page559. Original image from Fig. 3A. Artwork byLewis Long.

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