WHAT WE'RE READING

1383 A Sampling of Highlights from the Literature

CANCER IMMUNOLOGY AT THECROSSROADS

1384 Protective Innate Immune Variants in Racial/EthnicDisparities of Breast and Prostate CancerSusan T. Yeyeodu, LaCreis R. Kidd, and K. Sean Kimbro

CANCER IMMUNOLOGY MINIATURES

1390 Immunologic Correlates of Pathologic CompleteResponse to Preoperative Immunotherapy inHepatocellular CarcinomaAhmed Omar Kaseb, Luis Vence, Jorge Blando,Shalini S. Yadav, Naruhiko Ikoma,Roberto Carmagnani Pestana, Jean Nicolas Vauthey,James P. Allison, and Padmanee SharmaThis case report of a patient with hepatocellular carcinomahighlights the immune infiltrates that correlate with thecomplete pathologic response achieved after preoperativeanti–PD-1/CTLA-4. An increase in two distinct effector T-cellpopulations was observed.

1396 PD-1 Inhibition Achieves a Complete MetabolicResponse in a Patient with Malignant PeripheralNerve Sheath TumorLisa E. Davis, Lauren A. Nicholls, Hani M. Babiker, Joy Liau,and Daruka MahadevanHigh-grade malignant peripheral nerve sheath tumors have a poorprognosis with limited responsiveness to systemic therapy.Treatment with pembrolizumab resulted in a complete metabolicresponse after four cycles of therapy.

RESEARCH ARTICLES

1401 Immunologic Profiling of Mutational andTranscriptional Subgroups in Pediatric and AdultHigh-Grade GliomasMichael Bockmayr, Frederick Klauschen, Cecile L. Maire,Stefan Rutkowski, Manfred Westphal, Katrin Lamszus,Ulrich Sch€uller, and Malte MohmeAnalysis of the immune phenotype of rare molecular subgroups inpediatric and adult high-grade gliomas provides information thatmay increase the efficacy of immunotherapeutic approaches forpediatric and adolescent high-grade gliomas.

1412 Engineered Adoptive T-cell Therapy ProlongsSurvival in a Preclinical Model of Advanced-StageOvarian CancerKristin G. Anderson, Valentin Voillet, Breanna M. Bates,Edison Y. Chiu, Madison G. Burnett, Nicolas M. Garcia,Shannon K. Oda, Christopher B. Morse,Ingunn M. Stromnes, Charles W. Drescher,Raphael Gottardo, and Philip D. GreenbergOvarian cancer is the most lethal gynecologic cancer. High-affinityTCR-engineered T cells targeting mesothelin effectively kill humanovarian cancer lines and prolong survival of immunocompetentmice with advanced ovarian cancer, providing the basis for aplanned clinical trial.

1426 TGFb Programs Central Memory Differentiationin Ex Vivo–Stimulated Human T CellsAmina Dahmani, Val�erie Janelle, C�edric Carli,Manon Richaud, Caroline Lamarche, Myriam Khalili,Mathieu Goupil, Ksenia Bezverbnaya, Jonathan L. Bramson,and Jean-S�ebastien DelisleTGFb exposure during human T-cell stimulation ex vivo favorsearly memory differentiation and improves the function ofadoptively transferred T cells. TGFb signaling may, thus, beharnessed to manufacture early memory T cells for canceradoptive immunotherapy.

1440 Blockade of Immune-Checkpoint B7-H4 andLysine Demethylase 5B in Esophageal SquamousCell Carcinoma Confers Protective Immunityagainst P. gingivalis InfectionXiang Yuan, Yiwen Liu, Guifang Li, Zijun Lan, MingyangMa,Huaxu Li, Jinyu Kong, Jiangtao Sun, Gaochao Hou,Xurong Hou, Yingjian Ma, Feng Ren, Fuyou Zhou, andShegan GaoPorphyromonas gingivalis infection can increaseimmunosuppression and facilitate poor immunogenicity ofesophageal squamous cell carcinomas. Dual blockade of B7-H4and a histone demethylase controls P. gingivalis infection anddevelopment of associated tissue neoplasia.

1457 The Combined Effect of FGFR Inhibition and PD-1Blockade Promotes Tumor-Intrinsic Induction ofAntitumor ImmunitySangeetha Palakurthi, Mari Kuraguchi, Sima J. Zacharek,Enrique Zudaire, Wei Huang, Dennis M. Bonal, Jeffrey Liu,Abha Dhaneshwar, Kristin DePeaux, Martha R. Gowaski,Dyane Bailey, Samuel N. Regan, Elena Ivanova,Catherine Ferrante, Jessie M. English, Aditya Khosla,Andrew H. Beck, Julie A. Rytlewski, Catherine Sanders,Sylvie Laquerre, Mark A. Bittinger, Paul T. Kirschmeier,Kathryn Packman, Pasi A. Janne, Christopher Moy,Kwok-Kin Wong, Raluca I. Verona, and Matthew V. LorenziTreatments that use a pan-FGFR (fibroblast growth factorreceptor) inhibitor plus anti–PD-1 can boost antitumor responsesin tumors harboring genetic mutations in driver oncogenes. Theagents remodel the tumor microenvironment and enhance theexpansion of T-cell clones.

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September 2019 � Volume 7 � Issue 9

Cancer Immunology Research

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1472 MERTK Acts as a Costimulatory Receptor onHuman CD8þ T CellsMarlies J.W. Peeters, Donata Dulkeviciute, Arianna Draghi,Cathrin Ritter, Anne Rahbech, Signe K. Skadborg,Tina Seremet, Ana Micaela Carnaz Sim~oes,Evelina Martinenaite, Hólmfridur R. Halldórsdóttir,Mads Hald Andersen, Gitte Holmen Olofsson,Inge Marie Svane, Lene Juel Rasmussen, Özcan Met,J€urgen C. Becker, Marco Donia, Claus Desler, andPer thor StratenActivated CD8þ T cells express the MERTK receptor proteinkinase and its ligand PROS1. MERTK signaling acts as a latecostimulatory signal, improving CD8þ T-cell and TIL numbers,killing efficacy, and their secretion of memory and effectorcytokines.

1485 SLAMF6 as a Regulator of Exhausted CD8þ

T Cells in CancerBurcu Yigit, Ninghai Wang, Elisa ten Hacken,Shih-Shih Chen, Atul K. Bhan, Abel Suarez-Fueyo,Eri Katsuyama, George C. Tsokos, Nicholas Chiorazzi,Catherine J. Wu, Jan A. Burger, Roland W. Herzog,Pablo Engel, and Cox TerhorstSLAMF6 can be a target for modulating T-cell exhaustion.These data highlight the potential of targeting SLAMF6,either with single agents or in combination with otherinhibitors, to unleash CD8þ T-cell responses to improveimmunotherapy efficacy.

1497 Immune-Checkpoint Protein VISTA RegulatesAntitumor Immunity by Controlling MyeloidCell–Mediated Inflammation andImmunosuppressionWenwen Xu, Juan Dong, Yongwei Zheng, Juan Zhou,Ying Yuan, Hieu Minh Ta, Halli E. Miller, Michael Olson,Kamalakannan Rajasekaran, Marc S. Ernstoff,Demin Wang, Subramaniam Malarkannan, and Li WangVISTA is an immune-checkpoint protein that can regulatethe functions of MDSCs and DC subsets. Myeloid cellactivation precedes T cell–mediated antitumor responsesand, thus, contributes to the antitumor mechanisms ofVISTA inhibition.

1511 An RNA Aptamer–Based Biomarker PlatformDemonstrates High Soluble CD25 Occupancy byIL2 in the Serum of Follicular Lymphoma PatientsSuresh Veeramani, Sue E. Blackwell, William H. Thiel,Zhi-Zhang Yang, Stephen M. Ansell, Paloma H. Giangrande,and George J. WeinerAn aptamer-based technology to measure soluble ligand-receptorcomplexes in patient serum was developed and demonstrated usinglymphoma patients' sera to determine IL2–CD25 complexes.Similar approaches using this and other aptamer pairs could beused as a biomarker platform.

1523 An Anticancer Drug Cocktail of Three KinaseInhibitors Improved Response to a DendriticCell–Based Cancer VaccineJitao Guo, Elena Muse, Allison J. Christians,Steven J. Swanson, and Eduardo DavilaKinase inhibitors were screened for their ability to improve DCimmunogenicity. Combination treatment with three suchinhibitors (MK2206, NU7441, and trametinib) enhancesDC immunogenicity, improving anticancer responses from patient-derived T cells and in a mouse glioblastoma model.

1535 Accumulation of Tumor-Infiltrating CD49aþ NKCells Correlates with Poor Prognosis for HumanHepatocellular CarcinomaHaoyu Sun, Lianxin Liu, Qiang Huang, Huan Liu,Mei Huang, Jiabei Wang, Hao Wen, Renyong Lin, Kun Qu,Kun Li, Haiming Wei, Weihua Xiao, Rui Sun, Zhigang Tian,and Cheng SunAccumulation of CD49aþ NK cells in human hepatocellularcarcinoma (HCC) correlates with tumor growth and poorprognosis. This NK-cell subset may negatively regulate immuneresponses and promote the development of HCC.

1547 Natural Killer Cell Recruitment and ActivationAre Regulated by CD47 Expression in theTumor MicroenvironmentPulak Ranjan Nath, Dipasmita Pal-Nath, Ajeet Mandal,Margaret C. Cam, Anthony L. Schwartz, andDavid D. RobertsIdentification of NK-cell immune checkpoints in the tumormicroenvironment could provide a basis for improving melanomatreatment. CD47 expression regulated intratumoral and systemicNK-cell function, with blockade of CD47 improving antitumorNK-cell responses in melanoma.

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ABOUT THE COVER

Ovarian tumors are difficult to treat, andmore than half of patients with high-gradeserous ovarian carcinoma (HGSOC) diewithin 5 years. Three quarters of thesetumors overexpress mesothelin. Andersonet al. find that human T cells that expressan engineered T-cell receptor specific formesothelin can kill multiple HGSOC celllines. To study the effectiveness ofmesothelin-specific engineered T cellsin vivo, a mouse model was evaluated forresemblance to human HGSOC. Themouse peritoneal-cavity metastatictumors have a transcriptome profilesimilar to human metastatic tumors,including upregulation of multipleinhibitory pathways present in HGSOC.Mouse mesothelin-specific T cellsrecognize and kill ovarian cancer cellsin vitro and accumulate in the tumors, andco-infusion with a mesothelin peptidevaccine promotes expansion and increasesT-cell persistence. The presence of activetumor-specific engineered T cellscorrelates with tumor killing andprolonged mouse survival. This model isuseful for testing immunologicinterventions for patients with HGSOCand already serves as the basis for a clinicaltrial. Read more starting on page 1412.Original fluorescence micrograph of theovarian tumor microenvironmentprovided by the Greenberg laboratory.Artwork by Lewis Long.

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2019;7:1383-1561. Cancer Immunol Res     7 (9)

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