WHAT WE'RE READING

1037 A Sampling of Highlights from the Literature

MILESTONES IN CANCER IMMUNOLOGY

1038 The Seventh Annual AACR-CRI Lloyd J. OldAward in Cancer Immunology

CANCER IMMUNOLOGY AT THECROSSROADS

1040 Recharacterizing Tumor-Infiltrating Lymphocytesby Single-Cell RNA SequencingLei Zhang and Zemin Zhang

CANCER IMMUNOLOGY MINIATURES

1047 BCMA-Targeted CAR T-cell Therapy plusRadiotherapy for the Treatment of RefractoryMyeloma Reveals Potential SynergyEric L. Smith, Sham Mailankody, Mette Staehr,Xiuyan Wang, Brigitte Senechal, Terence J. Purdon,Anthony F. Daniyan, Mark B. Geyer, Aaron D. Goldberg,Elena Mead, Bianca D. Santomasso, Jonathan Landa,Andreas Rimner, Isabelle Riviere, Ola Landgren, andRenier J. BrentjensFavorable response of advanced MM was seen in one patientgiven CAR T-cell therapy followed by localized radiationtherapy. That TCR clonal expansion and CRS-like findingsoccurred after radiation therapy suggests synergy between thesetreatment modalities.

RESEARCH ARTICLES

1054 RORg Agonists Enhance the Sustained AntitumorActivity through Intrinsic Tc17 Cytotoxicity and Tc1RecruitmentXikui Liu, Elizabeth M. Zawidzka, Hongxiu Li,Charles A. Lesch, JennaDunbar, Dick Bousley,Weiping Zou,Xiao Hu, and Laura L. CarterTumor evasion can ensue from too few infiltrating cytotoxicT cells—type 1 (Tc1) or 17 (Tc17)—or infiltration ofdysfunctional effectors. RORg agonists augmented Tc17survival and lytic activity and directed recruitment of otherfunctional effector cells.

1064 Targeting Hypoxia-Induced Carbonic Anhydrase IXEnhances Immune-Checkpoint Blockade Locallyand SystemicallyShawn C. Chafe, Paul C. McDonald, Saeed Saberi,Oksana Nemirovsky, Geetha Venkateswaran,Samantha Burugu, Dongxia Gao, Alberto Delaidelli,Alastair H. Kyle, Jennifer H.E. Baker, Jordan A. Gillespie,Ali Bashashati, Andrew I. Minchinton, Youwen Zhou,Sohrab P. Shah, and Shoukat DedharThe prognosis for breast cancer and melanoma patients is worse iftheir tumors metabolically regulate pH, promoting an acidicmicroenvironment, through enzymes like CAIX. Inhibition ofCAIX plus blockade of immune checkpoints boosts antitumorresponses by buffering acidosis.

1079 Hypoxia-Induced VISTA Promotes the SuppressiveFunction of Myeloid-Derived Suppressor Cells inthe Tumor MicroenvironmentJie Deng, Jiannan Li, Aurelien Sarde, J. Louise Lines,Yu-Chi Lee, David C. Qian, Dov A. Pechenick,Richard Manivanh, Isabelle Le Mercier,Christopher H. Lowrey, Frederick S. Varn, Chao Cheng,David A. Leib, Randolph J. Noelle, and Rodwell MabaeraVISTA, induced on MDSCs by hypoxia in the tumormicroenvironment, enhances suppression of both CD4þ andCD8þ T cells. This mechanism of hypoxia-driven immuneescape and checkpoint resistance suggests a translatableapproach to combination therapies.

1091 Tumor Cells Hijack Macrophage-ProducedComplement C1q to Promote Tumor GrowthLubka T. Roumenina, Marie V. Daugan, R�emi No�e,Florent Petitprez, Yann A. Vano, Rafa€el Sanchez-Salas,Etienne Becht, Julie Meilleroux, B�en�edicte Le Clec'h,Nicolas A. Giraldo, Nicolas S. Merle, Cheng-Ming Sun,Virginie Verkarre, Pierre Validire, Janick Selves,Laetitia Lacroix, Olivier Delfour, Isabelle Vandenberghe,Celine Thuilliez, Sonia Keddani, Imene B. Sakhi, Eric Barret,Pierre Ferr�e, Nathalie Corvaïa, Alexandre Passioukov,Eric Chetaille, Marina Botto, Aur�elien de Reynies,StephaneMarie Oudard, ArnaudMejean, Xavier Cathelineau,Catherine Saut�es-Fridman, and Wolf H. FridmanThe density of C1q-producing TAMs and C4d deposits, hallmarksof complement activation, are negative prognostic factors in humanclear-cell renal cell carcinoma. Thus, the classical complementpathway is a potential therapeutic target for this cancer.

1106 Combination Therapy for Treating AdvancedDrug-Resistant Acute Lymphoblastic LeukemiaYorleny Vicioso, Hermann Gram, Rose Beck,Abhishek Asthana, Keman Zhang, Derek P. Wong,John Letterio, and Reshmi ParameswaranBlocking BAFF-R early in ALL promotes killing of leukemic cells.However, if given at later disease stages, efficacy is limited due toTGFb. Combining VAY736 and a TGFbR1 inhibitor improvedtreatment efficacy in advanced and drug-resistant ALL.

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July 2019 � Volume 7 � Issue 7

Cancer Immunology Research

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1120 Inhibition of the NKp44-PCNA ImmuneCheckpoint Using a mAb to PCNAKiran Kundu, Susmita Ghosh, Rhitajit Sarkar, Avishay Edri,Michael Brusilovsky, Orly Gershoni-Yahalom, Rami Yossef,Avishai Shemesh, Jean-Charles Soria, Vladimir Lazar,Ben-Zion Joshua, Kerry S. Campbell, Moshe Elkabets, andAngel PorgadorAn immune checkpoint blocking antibody was developed againstcancer cell surface PCNA, a ligand for NK-cell protein NKp44.Tests of the antibody in mice bearing patient-derived xenograftsshowed promise for overcoming tumor resistance toimmunotherapy.

1135 Targeting the YB-1/PD-L1 Axis to EnhanceChemotherapy and Antitumor ImmunityZhen Tao, Hailong Ruan, Lin Sun, Dong Kuang,Yongchun Song, Qi Wang, Tao Wang, Yi Hao, and Ke ChenThe YB-1 signaling axis promotes tumor immune evasion andmultidrug resistance. When targeted, chemoresistance decreasedand antitumor responses were enhanced, suggesting an avenue fortreating tumor multidrug resistance and immunosuppressivetumor microenvironments.

1148 Reduced Neoantigen Expression Revealed byLongitudinal Multiomics as a Possible ImmuneEvasion Mechanism in GliomaTakahide Nejo, Hirokazu Matsushita, Takahiro Karasaki,Masashi Nomura, Kuniaki Saito, Shota Tanaka,Shunsaku Takayanagi, Taijun Hana, Satoshi Takahashi,Yosuke Kitagawa, Tsukasa Koike, Yukari Kobayashi,Genta Nagae, Shogo Yamamoto, Hiroki Ueda,Kenji Tatsuno, Yoshitaka Narita, Motoo Nagane,Keisuke Ueki, Ryo Nishikawa, Hiroyuki Aburatani,Akitake Mukasa, Nobuhito Saito, and Kazuhiro KakimiWhole exome and RNA sequencing of paired primary andrecurrent glioma specimens revealed decreased neoantigenexpression at recurrence. Evidence of persistent immune responsessuggests immune selection pressure as a possible mechanism,despite treatment with standard, nonimmune-based regimens.

1162 A Gene Signature Predicting Natural Killer CellInfiltration and Improved Survival in MelanomaPatientsJoseph Cursons, Fernando Souza-Fonseca-Guimaraes,Momeneh Foroutan, Ashley Anderson, Fr�ed�eric Hollande,Soroor Hediyeh-Zadeh, Andreas Behren,Nicholas D. Huntington, and Melissa J. DavisInnate immunity can provide new targets for immunotherapy.Singscore, a gene-set scoring method, revealed that NK cellinfiltration correlated with improved patient survival rates.Stromal and tumor elements, as well as cytokines involved inNK function were investigated.

1175 CCR4 Blockade Depletes Regulatory T Cells andProlongs Survival in a Canine Model of BladderCancerShingo Maeda, Kohei Murakami, Akiko Inoue,Tomohiro Yonezawa, and Naoaki MatsukiAnti-CCR4 treatment to target regulatory T cells induced clinicalresponses and prolonged survival in dogs with spontaneous bladdercancer. Expression of CCR4 in human tumor samples suggeststranslational relevance for treatment of bladder cancer in humans.

1188 An Artificial Antigen-Presenting Cell Delivering 11Immune Molecules Expands Tumor Antigen–Specific CTLs in Ex Vivo and In Vivo MurineMelanoma ModelsLei Zhang, Shilong Song, Xiaoxiao Jin, Xin Wan,Khawar Ali Shahzad, Weiya Pei, Chen Zhao, andChuanlai ShenMultipotent microparticles bearing T-cell antigens andcostimulatory molecules—and containing cytokines, chemokines,and checkpoint inhibitors—were injected intravenously intomelanoma-bearing mice. These particles inhibited melanomagrowth and expanded tumor-specific CTLs in peripheral blood,spleen, and tumor tissue.

1202 HPV Epitope Processing Differences Correlatewith ERAP1 Allotype and Extent of CD8þ T-cellTumor Infiltration in OPSCCEmma Reeves, Oliver Wood, Christian H. Ottensmeier,Emma V. King, Gareth J. Thomas, Tim Elliott, andEdward JamesThe ability to generate HPV-derived peptide antigens is governedby which ERAP1 molecules are expressed. Thus HPVþ

OPSCC patients have different numbers of tumor-infiltratingCD8þ T cells, which affects disease progression.

1214 The Impact of High-Dose Glucocorticoids on theOutcome of Immune-Checkpoint Inhibitor–Related Thyroid DisordersChanjuan Ma, F. Stephen Hodi, Anita Giobbie-Hurder,Xiaocheng Wang, Jing Zhou, Amy Zhang, Ying Zhou,Fei Mao, Trevor E. Angell, Chelsea P. Andrews, Jiani Hu,Romualdo Barroso-Sousa, Ursula B. Kaiser, SaraM. Tolaney,and Le MinThyroid disorders are common immune-related adverse events,and improved clinical management is needed. In this study, highdose glucocorticoids did not improve duration of thyrotoxicosis oronset of hypothyroidism in patients treated with immunecheckpoint inhibitors.

CORRECTION

1221 Correction: Performance Evaluation of MHC Class-IBindingPredictionTools BasedonanExperimentallyValidated MHC–Peptide Binding Data Set

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ABOUT THE COVER

The tumor microenvironment is comprised ofseveral factors that can limit antitumorresponses. One such factor is low pH, whichresults in an acidic environment that candampen immune responses. Carbonicanhydrase IX (CAIX) is a hypoxia-inducedregulatory enzyme that can modulateextracellular pH. Chafe et al. show that thisenzyme is associated with risk ofmetastasis andworse overall outcome in patients withmelanoma. Targeting CAIX with a small-molecule inhibitor alleviates extracellularacidification by altering the glycolyticmetabolism of melanoma cells, allowingantitumor responses to ensue. Combining theCAIX-targeting small-molecule inhibitor withimmune checkpoint blockade in breast cancerandmelanomamodels sensitizes the tumors tothe therapy, boosts antitumor responses, andreduces tumor growth and metastases. Thesedata highlight how targeting CAIX in solidtumors is a potential strategy to improvetherapeutic responses and survival of patients.Read more in this issue on page 1064. Originalimage from Fig. 1A. Artwork by Lewis Long.

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2019;7:1037-1221. Cancer Immunol Res     7 (7)

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