bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Tumor ENPP1 (CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer
Authors: Ruiz-Fernández de Córdoba Borja , Moreno Haritz , Valencia Karmele , Perurena Naiara , Ruedas Pablo , Walle Thomas , Pezonaga-Torres Alberto , Hinojosa Juan , Guruceaga Elisabet , Pineda-Lucena Antonio , Abengózar-Muela Marta , Cochonneau Denis , Zandueta Carolina , Martínez-Canarias Susana , Teijeira Álvaro , Ajona Daniel , Ortiz-Espinosa Sergio , Morales Xabier , Ortiz de Solórzano Carlos , Santisteban Marta , Ramos-García Luis I. , Guembe Laura , Strnad Vratislav , Heymann Dominique , Hervás-Stubbs Sandra , Pío Rubén , Rodríguez-Ruiz María E. , de Andrea Carlos E. , Vicent Silvestre , Melero Ignacio , Lecanda Fernando , Martínez-Monge Rafael
Published: April 2023

Abstract
Locoregional failure (LRF) in patients with breast cancer post-surgery and post-irradiation is linked to a dismal prognosis. In a refined new model, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1/CD203a (ENPP1) to be closely associated with LRF. ENPP1hi circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of polymorphonuclear myeloid-derived suppressor cells and neutrophil extracellular trap (NET) formation. Genetic and pharmacologic ENPP1 inhibition or NET blockade extends relapse-free survival. Furthermore, in combination with fractionated irradiation, ENPP1 abrogation obliterates LRF. Mechanistically, ENPP1-generated adenosinergic metabolites enhance haptoglobin (HP) expression. This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.
Significance:
CTC exploit the ENPP1/HP axis to promote local recurrence post-surgery and post-irradiation by subduing myeloid suppressor cells in breast tumors. Blocking this axis impairs tumor engraftment, impedes immunosuppression, and obliterates NET formation, unveiling new opportunities for therapeutic intervention to eradicate local relapse and ameliorate patient survival.

This article is highlighted in the In This Issue feature, p. 1171
Data from Stress Granules Determine the Development of Obesity-Associated Pancreatic Cancer
Authors: Fonteneau Guillaume , Redding Alexandra , Hoag-Lee Hannah , Sim Edward S. , Heinrich Stefan , Gaida Matthias M. , Grabocka Elda
Published: April 2023

Abstract
Obesity is a global epidemic and a major predisposing factor for cancer. Increasing evidence shows that obesity-associated stress is a key driver of cancer risk and progression. Previous work has identified the phase-separation organelles,﻿ stress granules (SG), as mutant KRAS–dependent mediators of stress adaptation. However, the dependence of tumorigenesis on these organelles is unknown. Here, we establish a causal link between SGs and pancreatic ductal adenocarcinoma (PDAC). Importantly, we uncover that dependence on SGs is drastically heightened in obesity-associated PDAC. Furthermore, we identify a previously unknown regulator and component of SGs, namely, the serine/arginine protein kinase 2 (SRPK2), as a specific determinant of SG formation in obesity-associated PDAC. We show that SRPK2-mediated SG formation in obesity-associated PDAC is driven by hyperactivation of the IGF1/PI3K/mTOR/S6K1 pathway and that S6K1 inhibition selectively attenuates SGs and impairs obesity-associated PDAC development.
Significance:
We show that stress adaptation via the phase-separation organelles SGs mediates PDAC development. Moreover, preexisting stress conditions such as obesity are a driving force behind tumor SG dependence, and enhanced SG levels are key determinants and a chemopreventive target for obesity-associated PDAC.

This article is highlighted in the In This Issue feature, p. 1825
Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Authors: Chandra Bappaditya , Michmerhuizen Nicole L. , Shirnekhi Hazheen K. , Tripathi Swarnendu , Pioso Brittany J. , Baggett David W. , Mitrea Diana M. , Iacobucci Ilaria , White Michael R. , Chen Jingjing , Park Cheon-Gil , Wu Huiyun , Pounds Stanley , Medyukhina Anna , Khairy Khaled , Gao Qingsong , Qu Chunxu , Abdelhamed Sherif , Gorman Scott D. , Bawa Simranjot , Maslanka Carolyn , Kinger Swati , Dogra Priyanka , Ferrolino Mylene C. , Di Giacomo Danika , Mecucci Cristina , Klco Jeffery M. , Mullighan Charles G. , Kriwacki Richard W.
Published: April 2023

Abstract
NUP98 fusion oncoproteins (FO) are drivers in pediatric leukemias and many transform hematopoietic cells. Most NUP98 FOs harbor an intrinsically disordered region from NUP98 that is prone to liquid–liquid phase separation (LLPS) in vitro. A predominant class of NUP98 FOs, including NUP98–HOXA9 (NHA9), retains a DNA-binding homeodomain, whereas others harbor other types of DNA- or chromatin-binding domains. NUP98 FOs have long been known to form puncta, but long-standing questions are how nuclear puncta form and how they drive leukemogenesis. Here we studied NHA9 condensates and show that homotypic interactions and different types of heterotypic interactions are required to form nuclear puncta, which are associated with aberrant transcriptional activity and transformation of hematopoietic stem and progenitor cells. We also show that three additional leukemia-associated NUP98 FOs (NUP98–PRRX1, NUP98–KDM5A, and NUP98–LNP1) form nuclear puncta and transform hematopoietic cells. These findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs.
Significance:
We show that homotypic and heterotypic mechanisms of LLPS control NUP98–HOXA9 puncta formation, modulating transcriptional activity and transforming hematopoietic cells. Importantly, these mechanisms are generalizable to other NUP98 FOs that share similar domain structures. These findings address long-standing questions on how nuclear puncta form and their link to leukemogenesis.

This article is highlighted in the In This Issue feature, p. 873
Data from A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti–PD-1 Resistance through Effects on the Gut Microbiota
Authors: Messaoudene Meriem , Pidgeon Reilly , Richard Corentin , Ponce Mayra , Diop Khoudia , Benlaifaoui Myriam , Nolin-Lapalme Alexis , Cauchois Florent , Malo Julie , Belkaid Wiam , Isnard Stephane , Fradet Yves , Dridi Lharbi , Velin Dominique , Oster Paul , Raoult Didier , Ghiringhelli François , Boidot Romain , Chevrier Sandy , Kysela David T. , Brun Yves V. , Falcone Emilia Liana , Pilon Geneviève , Oñate Florian Plaza , Gitton-Quent Oscar , Le Chatelier Emmanuelle , Durand Sylvere , Kroemer Guido , Elkrief Arielle , Marette André , Castagner Bastien , Routy Bertrand
Published: April 2023

Abstract
Several approaches to manipulate the gut microbiome for improving the activity of cancer immune-checkpoint inhibitors (ICI) are currently under evaluation. Here, we show that oral supplementation with the polyphenol-rich berry camu-camu (CC; Myrciaria dubia) in mice shifted gut microbial composition, which translated into antitumor activity and a stronger anti–PD-1 response. We identified castalagin, an ellagitannin, as the active compound in CC. Oral administration of castalagin enriched for bacteria associated with efficient immunotherapeutic responses (Ruminococcaceae and Alistipes) and improved the CD8+/FOXP3+CD4+ ratio within the tumor microenvironment. Moreover, castalagin induced metabolic changes, resulting in an increase in taurine-conjugated bile acids. Oral supplementation of castalagin following fecal microbiota transplantation from ICI-refractory patients into mice supported anti–PD-1 activity. Finally, we found that castalagin binds to Ruminococcus bromii and promoted an anticancer response. Altogether, our results identify castalagin as a polyphenol that acts as a prebiotic to circumvent anti–PD-1 resistance.
Significance:
The polyphenol castalagin isolated from a berry has an antitumor effect through direct interactions with commensal bacteria, thus reprogramming the tumor microenvironment. In addition, in preclinical ICI-resistant models, castalagin reestablishes the efficacy of anti–PD-1. Together, these results provide a strong biological rationale to test castalagin as part of a clinical trial.

This article is highlighted in the In This Issue feature, p. 873
Data from BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL
Authors: Xia Min , David Liron , Teater Matt , Gutierrez Johana , Wang Xiang , Meydan Cem , Lytle Andrew , Slack Graham W. , Scott David W. , Morin Ryan D. , Onder Ozlem , Elenitoba-Johnson Kojo S.J. , Zamponi Nahuel , Cerchietti Leandro , Lu Tianbao , Philippar Ulrike , Fontan Lorena , Wu Hao , Melnick Ari M.
Published: April 2023

Abstract
Activated B cell–like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11–BCL10–MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes.
Significance:
ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure–function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs.

See related commentary by Phelan and Oellerich, p. 1844.

This article is highlighted in the In This Issue feature, p. 1825
Data from Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability
Authors: Thomas Daniel , Wu Manhong , Nakauchi Yusuke , Zheng Ming , Thompson-Peach Chloe A.L. , Lim Kelly , Landberg Niklas , Köhnke Thomas , Robinson Nirmal , Kaur Satinder , Kutyna Monika , Stafford Melissa , Hiwase Devendra , Reinisch Andreas , Peltz Gary , Majeti Ravindra
Published: April 2023

Abstract
Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme [acetyl CoA carboxylase 1 (ACC1)] as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified an mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to b-oxidation indicating reprogramming of metabolism toward a reliance on fatty acids. Compared with mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ hematopoietic stem/progenitor cells or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in the growth inhibition of mIDH1 cancers not reversible by ivosidenib. Critically, the pharmacologic targeting of ACC1 improved the sensitivity of mIDH1 AML to venetoclax.
Significance:
Oncogenic mutations in both IDH1 and IDH2 produce 2-hydroxyglutarate and are generally considered equivalent in terms of pathogenesis and targeting. Using comprehensive metabolomic analysis, we demonstrate unexpected metabolic differences in fatty acid metabolism between mutant IDH1 and IDH2 in patient samples with targetable metabolic interventions.

See related commentary by Robinson and Levine, p. 266.

This article is highlighted in the In This Issue feature, p. 247
Data from Bone Metastasis Initiation Is Coupled with Bone Remodeling through Osteogenic Differentiation of NG2+ Cells
Authors: Zhang Weijie , Xu Zhan , Hao Xiaoxin , He Tiancheng , Li Jiasong , Shen Yichao , Liu Kai , Gao Yang , Liu Jun , Edwards David G. , Muscarella Aaron M. , Wu Ling , Yu Liqun , Xu Longyong , Chen Xi , Wu Yi-Hsuan , Bado Igor L. , Ding Yunfeng , Aguirre Sergio , Wang Hai , Gugala Zbigniew , Satcher Robert L. , Wong Stephen T.C. , Zhang Xiang H.-F.
Published: April 2023

Abstract
The bone microenvironment is dynamic and undergoes remodeling in normal and pathologic conditions. Whether such remodeling affects disseminated tumor cells (DTC) and bone metastasis remains poorly understood. Here, we demonstrated that pathologic fractures increase metastatic colonization around the injury. NG2+ cells are a common participant in bone metastasis initiation and bone remodeling in both homeostatic and fractured conditions. NG2+ bone mesenchymal stem/stromal cells (BMSC) often colocalize with DTCs in the perivascular niche. Both DTCs and NG2+ BMSCs are recruited to remodeling sites. Ablation of NG2+ lineage impaired bone remodeling and concurrently diminished metastatic colonization. In cocultures, NG2+ BMSCs, especially when undergoing osteodifferentiation, enhanced cancer cell proliferation and migration. Knockout of N-cadherin in NG2+ cells abolished these effects in vitro and phenocopied NG2+ lineage depletion in vivo. These findings uncover dual roles of NG2+ cells in metastasis and remodeling and indicate that osteodifferentiation of BMSCs promotes metastasis initiation via N-cadherin–mediated cell–cell interaction.
Significance:
The bone colonization of cancer cells occurs in an environment that undergoes constant remodeling. Our study provides mechanistic insights into how bone homeostasis and pathologic repair lead to the outgrowth of disseminated cancer cells, thereby opening new directions for further etiologic and epidemiologic studies of tumor recurrences.

This article is highlighted in the In This Issue feature, p. 247
Data from Distinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti–PD-1 Immunotherapy in Endometrial Carcinoma
Authors: Chow Ryan D. , Michaels Tai , Bellone Stefania , Hartwich Tobias M.P. , Bonazzoli Elena , Iwasaki Akiko , Song Eric , Santin Alessandro D.
Published: April 2023

Abstract
Mismatch repair–deficient (MMRd) cancers have varied responses to immune-checkpoint blockade (ICB). We conducted a phase II clinical trial of the PD-1 inhibitor pembrolizumab in 24 patients with MMRd endometrial cancer (NCT02899793). Patients with mutational MMRd tumors (6 patients) had higher response rates and longer survival than those with epigenetic MMRd tumors (18 patients). Mutation burden was higher in tumors with mutational MMRd compared with epigenetic MMRd; however, within each category of MMRd, mutation burden was not correlated with ICB response. Pretreatment JAK1 mutations were not associated with primary resistance to pembrolizumab. Longitudinal single-cell RNA-seq of circulating immune cells revealed contrasting modes of antitumor immunity for mutational versus epigenetic MMRd cancers. Whereas effector CD8+ T cells correlated with regression of mutational MMRd tumors, activated CD16+ NK cells were associated with ICB-responsive epigenetic MMRd tumors. These data highlight the interplay between tumor-intrinsic and tumor-extrinsic factors that influence ICB response.
Significance:
The molecular mechanism of MMRd is associated with response to anti–PD-1 immunotherapy in endometrial carcinoma. Tumors with epigenetic MMRd or mutational MMRd are correlated with NK cell or CD8+ T cell–driven immunity, respectively. Classifying tumors by the mechanism of MMRd may inform clinical decision-making regarding cancer immunotherapy.

This article is highlighted in the In This Issue feature, p. 247
Data from A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma
Authors: Rappold Phillip M. , Vuong Lynda , Leibold Josef , Chakiryan Nicholas H. , Curry Michael , Kuo Fengshen , Sabio Erich , Jiang Hui , Nixon Briana G. , Liu Ming , Berglund Anders E. , Silagy Andrew W. , Mascareno Eduardo A. , Golkaram Mahdi , Marker Mahtab , Reising Albert , Savchenko Alexander , Millholland John , Chen Ying-Bei , Russo Paul , Coleman Jonathan , Reznik Ed , Manley Brandon J. , Ostrovnaya Irina , Makarov Vladimir , DiNatale Renzo G. , Blum Kyle A. , Ma Xiaoxiao , Chowell Diego , Li Ming O. , Solit David B. , Lowe Scott W. , Chan Timothy A. , Motzer Robert J. , Voss Martin H. , Hakimi A. Ari
Published: April 2023

Abstract
It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC.
Significance:
Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model.

This article is highlighted in the In This Issue feature, p. 2221
Data from MinimuMM-seq: Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology
Authors: Dutta Ankit K. , Alberge Jean-Baptiste , Lightbody Elizabeth D. , Boehner Cody J. , Dunford Andrew , Sklavenitis-Pistofidis Romanos , Mouhieddine Tarek H. , Cowan Annie N. , Su Nang Kham , Horowitz Erica M. , Barr Hadley , Hevenor Laura , Beckwith Jenna B. , Perry Jacqueline , Cao Amanda , Lin Ziao , Kuhr Frank K. , Mastro Richard G. Del , Nadeem Omar , Greipp Patricia T. , Stewart Chip , Auclair Daniel , Getz Gad , Ghobrial Irene M.
Published: April 2023

Abstract
Multiple myeloma (MM) develops from well-defined precursor stages; however, invasive bone marrow (BM) biopsy limits screening and monitoring strategies for patients. We enumerated circulating tumor cells (CTC) from 261 patients (84 monoclonal gammopathy of undetermined significance, 155 smoldering multiple myeloma, and 22 MM), with neoplastic cells detected in 84%. We developed a novel approach, MinimuMM-seq, which enables the detection of translocations and copy-number abnormalities through whole-genome sequencing of highly pure CTCs. Application to CTCs in a cohort of 51 patients, 24 with paired BM, was able to detect 100% of clinically reported BM biopsy events and could replace molecular cytogenetics for diagnostic yield and risk classification. Longitudinal sampling of CTCs in 8 patients revealed major clones could be tracked in the blood, with clonal evolution and shifting dynamics of subclones over time. Our findings provide proof of concept that CTC detection and genomic profiling could be used clinically for monitoring and managing disease in MM.
Significance:
In this study, we established an approach enabling the enumeration and sequencing of CTCs to replace standard molecular cytogenetics. CTCs harbored the same pathognomonic MM abnormalities as BM plasma cells. Longitudinal sampling of serial CTCs was able to track clonal dynamics over time and detect the emergence of high-risk genetic subclones.

This article is highlighted in the In This Issue feature, p. 247
Data from Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade
Authors: Lander Varintra E. , Belle Jad I. , Kingston Natalie L. , Herndon John M. , Hogg Graham D. , Liu Xiuting , Kang Liang-I , Knolhoff Brett L. , Bogner Savannah J. , Baer John M. , Zuo Chong , Borcherding Nicholas C. , Lander Daniel P. , Mpoy Cedric , Scott Jalen , Zahner Michael , Rogers Buck E. , Schwarz Julie K. , Kim Hyun , DeNardo David G.
Published: April 2023

Abstract
The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T-cell priming. Using in vitro systems, we found that tumor–stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy in vitro and in vivo, leading to tumor regression, T-cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival.
Significance:
Checkpoint immunotherapeutics have not been effective in PDAC, even when combined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy.

This article is highlighted in the In This Issue feature, p. 2711
Data from OncoLoop: A Network-Based Precision Cancer Medicine Framework
Authors: Vasciaveo Alessandro , Arriaga Juan Martín , de Almeida Francisca Nunes , Zou Min , Douglass Eugene F. , Picech Florencia , Shibata Maho , Rodriguez-Calero Antonio , de Brot Simone , Mitrofanova Antonina , Chua Chee Wai , Karan Charles , Realubit Ronald , Pampou Sergey , Kim Jaime Y. , Afari Stephanie N. , Mukhammadov Timur , Zanella Luca , Corey Eva , Alvarez Mariano J. , Rubin Mark A. , Shen Michael M. , Califano Andrea , Abate-Shen Cory
Published: April 2023

Abstract
Prioritizing treatments for individual patients with cancer remains challenging, and performing coclinical studies using patient-derived models in real time is often unfeasible. To circumvent these challenges, we introduce OncoLoop, a precision medicine framework that predicts drug sensitivity in human tumors and their preexisting high-fidelity (cognate) model(s) by leveraging drug perturbation profiles. As a proof of concept, we applied OncoLoop to prostate cancer using genetically engineered mouse models (GEMM) that recapitulate a broad spectrum of disease states, including castration-resistant, metastatic, and neuroendocrine prostate cancer. Interrogation of human prostate cancer cohorts by Master Regulator (MR) conservation analysis revealed that most patients with advanced prostate cancer were represented by at least one cognate GEMM-derived tumor (GEMM-DT). Drugs predicted to invert MR activity in patients and their cognate GEMM-DTs were successfully validated in allograft, syngeneic, and patient-derived xenograft (PDX) models of tumors and metastasis. Furthermore, OncoLoop-predicted drugs enhanced the efficacy of clinically relevant drugs, namely, the PD-1 inhibitor nivolumab and the AR inhibitor enzalutamide.
Significance:
OncoLoop is a transcriptomic-based experimental and computational framework that can support rapid-turnaround coclinical studies to identify and validate drugs for individual patients, which can then be readily adapted to clinical practice. This framework should be applicable in many cancer contexts for which appropriate models and drug perturbation data are available.

This article is highlighted in the In This Issue feature, p. 247
Data from A Dynamic rRNA Ribomethylome Drives Stemness in Acute Myeloid Leukemia
Authors: Zhou Fengbiao , Aroua Nesrine , Liu Yi , Rohde Christian , Cheng Jingdong , Wirth Anna-Katharina , Fijalkowska Daria , Göllner Stefanie , Lotze Michelle , Yun Haiyang , Yu Xiaobing , Pabst Caroline , Sauer Tim , Oellerich Thomas , Serve Hubert , Röllig Christoph , Bornhäuser Martin , Thiede Christian , Baldus Claudia , Frye Michaela , Raffel Simon , Krijgsveld Jeroen , Jeremias Irmela , Beckmann Roland , Trumpp Andreas , Müller-Tidow Carsten
Published: April 2023

Abstract
The development and regulation of malignant self-renewal remain unresolved issues. Here, we provide biochemical, genetic, and functional evidence that dynamics in ribosomal RNA (rRNA) 2′-O-methylation regulate leukemia stem cell (LSC) activity in vivo. A comprehensive analysis of the rRNA 2′-O-methylation landscape of 94 patients with acute myeloid leukemia (AML) revealed dynamic 2′-O-methylation specifically at exterior sites of ribosomes. The rRNA 2′-O-methylation pattern is closely associated with AML development stage and LSC gene expression signature. Forced expression of the 2′-O-methyltransferase fibrillarin (FBL) induced an AML stem cell phenotype and enabled engraftment of non-LSC leukemia cells in NSG mice. Enhanced 2′-O-methylation redirected the ribosome translation program toward amino acid transporter mRNAs enriched in optimal codons and subsequently increased intracellular amino acid levels. Methylation at the single site 18S-guanosine 1447 was instrumental for LSC activity. Collectively, our work demonstrates that dynamic 2′-O-methylation at specific sites on rRNAs shifts translational preferences and controls AML LSC self-renewal.
Significance:
We establish the complete rRNA 2′-O-methylation landscape in human AML. Plasticity of rRNA 2′-O-methylation shifts protein translation toward an LSC phenotype. This dynamic process constitutes a novel concept of how cancers reprogram cell fate and function.

This article is highlighted in the In This Issue feature, p. 247
Data from Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia
Authors: Reglero Clara , Dieck Chelsea L. , Zask Arie , Forouhar Farhad , Laurent Anouchka P. , Lin Wen-Hsuan W. , Albero Robert , Miller Hannah I. , Ma Cindy , Gastier-Foster Julie M. , Loh Mignon L. , Tong Liang , Stockwell Brent R. , Palomero Teresa , Ferrando Adolfo A.
Published: April 2023

Abstract
Low-intensity maintenance therapy with 6-mercaptopurine (6-MP) limits the occurrence of acute lymphoblastic leukemia (ALL) relapse and is central to the success of multiagent chemotherapy protocols. Activating mutations in the 5′-nucleotidase cytosolic II (NT5C2) gene drive resistance to 6-MP in over 35% of early relapse ALL cases. Here we identify CRCD2 as a first-in-class small-molecule NT5C2 nucleotidase inhibitor broadly active against leukemias bearing highly prevalent relapse-associated mutant forms of NT5C2 in vitro and in vivo. Importantly, CRCD2 treatment also enhanced the cytotoxic activity of 6-MP in NT5C2 wild-type leukemias, leading to the identification of NT5C2 Ser502 phosphorylation as a novel NT5C2-mediated mechanism of 6-MP resistance in this disease. These results uncover an unanticipated role of nongenetic NT5C2 activation as a driver of 6-MP resistance in ALL and demonstrate the potential of NT5C2 inhibitor therapy for enhancing the efficacy of thiopurine maintenance therapy and overcoming resistance at relapse.
Significance:
Relapse-associated NT5C2 mutations directly contribute to relapse in ALL by driving resistance to chemotherapy with 6-MP. Pharmacologic inhibition of NT5C2 with CRCD2, a first-in-class nucleotidase inhibitor, enhances the cytotoxic effects of 6-MP and effectively reverses thiopurine resistance mediated by genetic and nongenetic mechanisms of NT5C2 activation in ALL.

This article is highlighted in the In This Issue feature, p. 2483
Data from Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA
Authors: Cortes-Ciriano Isidro , Steele Christopher D. , Piculell Katherine , Al-Ibraheemi Alyaa , Eulo Vanessa , Bui Marilyn M. , Chatzipli Aikaterini , Dickson Brendan C. , Borcherding Dana C. , Feber Andrew , Galor Alon , Hart Jesse , Jones Kevin B. , Jordan Justin T. , Kim Raymond H. , Lindsay Daniel , Miller Colin , Nishida Yoshihiro , Proszek Paula Z. , Serrano Jonathan , Sundby R. Taylor , Szymanski Jeffrey J. , Ullrich Nicole J. , Viskochil David , Wang Xia , Snuderl Matija , Park Peter J. , Flanagan Adrienne M. , Hirbe Angela C. , Pillay Nischalan , Miller David T.
Published: April 2023

Abstract
Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis.
Significance:
MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups.

This article is highlighted in the In This Issue feature, p. 517
Data from NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance Mutations
Authors: Drilon Alexander , Horan Joshua C. , Tangpeerachaikul Anupong , Besse Benjamin , Ou Sai-Hong Ignatius , Gadgeel Shirish M. , Camidge D. Ross , van der Wekken Anthonie J. , Nguyen-Phuong Linh , Acker Adam , Keddy Clare , Nicholson Katelyn S. , Yoda Satoshi , Mente Scot , Sun Yuting , Soglia John R. , Kohl Nancy E. , Porter James R. , Shair Matthew D. , Zhu Viola , Davare Monika A. , Hata Aaron N. , Pelish Henry E. , Lin Jessica J.
Published: April 2023

Abstract
ROS1 tyrosine kinase inhibitors (TKI) have been approved (crizotinib and entrectinib) or explored (lorlatinib, taletrectinib, and repotrectinib) for the treatment of ROS1 fusion–positive cancers, although none of them simultaneously address the need for broad resistance coverage, avoidance of clinically dose-limiting TRK inhibition, and brain penetration. NVL-520 is a rationally designed macrocycle with >50-fold ROS1 selectivity over 98% of the kinome tested. It is active in vitro against diverse ROS1 fusions and resistance mutations and exhibits 10- to 1,000-fold improved potency for the ROS1 G2032R solvent-front mutation over crizotinib, entrectinib, lorlatinib, taletrectinib, and repotrectinib. In vivo, it induces tumor regression in G2032R-inclusive intracranial and patient-derived xenograft models. Importantly, NVL-520 has an ∼100-fold increased potency for ROS1 and ROS1 G2032R over TRK. As a clinical proof of concept, NVL-520 elicited objective tumor responses in three patients with TKI-refractory ROS1 fusion–positive lung cancers, including two with ROS1 G2032R and one with intracranial metastases, with no observed neurologic toxicities.
Significance:
The combined preclinical features of NVL-520 that include potent targeting of ROS1 and diverse ROS1 resistance mutations, high selectivity for ROS1 G2032R over TRK, and brain penetration mark the development of a distinct ROS1 TKI with the potential to surpass the limitations of earlier-generation TKIs for ROS1 fusion–positive patients.

This article is highlighted in the In This Issue feature, p. 517
Data from LZTR1 Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL
Authors: Ko Aram , Hasanain Mohammad , Oh Young Taek , D'Angelo Fulvio , Sommer Danika , Frangaj Brulinda , Tran Suzanne , Bielle Franck , Pollo Bianca , Paterra Rosina , Mokhtari Karima , Soni Rajesh Kumar , Peyre Matthieu , Eoli Marica , Papi Laura , Kalamarides Michel , Sanson Marc , Iavarone Antonio , Lasorella Anna
Published: April 2023

Abstract
LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1– and Cdkn2a-deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL coinhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1-mutant cancer.
Significance:
EGFR and AXL are substrates of LZTR1-CUL3 ubiquitin ligase. The frequent somatic and germline mutations of LZTR1 in human cancer cause EGFR and AXL accumulation and deregulated signaling. LZTR1-mutant tumors show vulnerability to concurrent inhibition of EGFR and AXL, thus providing precision targeting to patients affected by LZTR1-mutant cancer.

This article is highlighted in the In This Issue feature, p. 517
Data from Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia
Authors: Uckelmann Hannah J. , Haarer Elena L. , Takeda Reina , Wong Eric M. , Hatton Charlie , Marinaccio Christian , Perner Florian , Rajput Masooma , Antonissen Noa J.C. , Wen Yanhe , Yang Lu , Brunetti Lorenzo , Chen Chun-Wei , Armstrong Scott A.
Published: April 2023

Abstract
The dysregulation of developmental and stem cell–associated genes is a common phenomenon during cancer development. Around half of patients with acute myeloid leukemia (AML) express high levels of HOXA cluster genes and MEIS1. Most of these AML cases harbor an NPM1 mutation (NPM1c), which encodes for an oncoprotein mislocalized from the nucleolus to the cytoplasm. How NPM1c expression in hematopoietic cells leads to its characteristic gene-expression pattern remains unclear. Here, we show that NPM1c directly binds to specific chromatin targets, which are co-occupied by the histone methyltransferase KMT2A (MLL1). Targeted degradation of NPM1c leads to a rapid decrease in gene expression and loss of RNA polymerase II, as well as activating histone modifications at its targets. We demonstrate that NPM1c directly regulates oncogenic gene expression in collaboration with the MLL1 complex and define the mechanism by which MLL1–Menin small-molecule inhibitors produce clinical responses in patients with NPM1-mutated AML.
Significance:
We uncovered an important functional role of mutant NPM1 as a crucial direct driver of oncogenic gene expression in AML. NPM1c can bind to chromatin and cooperate with the MLL complex, providing the first functional insight into the mechanism of Menin–MLL inhibition in NPM1c leukemias.

See related article by Wang et al., p. 724.

This article is highlighted in the In This Issue feature, p. 517
Supplementary Figure 2 from Transient Complement Inhibition Promotes a Tumor-Specific Immune Response through the Implication of Natural Killer Cells
Authors: Janelle Valérie , Langlois Marie-Pierre , Tarrab Esther , Lapierre Pascal , Poliquin Laurent , Lamarre Alain
Published: April 2023

PDF file - 26K, Supplemental Figure 2. MDSC proportions following CVF treatment.
Supplementary Figure 1 from Transient Complement Inhibition Promotes a Tumor-Specific Immune Response through the Implication of Natural Killer Cells
Authors: Janelle Valérie , Langlois Marie-Pierre , Tarrab Esther , Lapierre Pascal , Poliquin Laurent , Lamarre Alain
Published: April 2023

PDF file - 24K, Supplementary Figure 1. Complement system inhibition by CVF.
Supplementary Table S3 from Phase II Study of Personalized Peptide Vaccination for Previously Treated Advanced Colorectal Cancer
Authors: Kibe Shiro , Yutani Shigeru , Motoyama Satoru , Nomura Takanobu , Tanaka Natsuki , Kawahara Akihiko , Yamaguchi Tomohiko , Matsueda Satoko , Komatsu Nobukazu , Miura Masatomo , Hinai Yudai , Hattori Satoshi , Yamada Akira , Kage Masayoshi , Itoh Kyogo , Akagi Yoshito , Sasada Tetsuro
Published: April 2023

Genetic polymorphisms.
Suppl Movie 8 from Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility
Authors: Pentcheva-Hoang Tsvetelina , Simpson Tyler R. , Montalvo-Ortiz Welby , Allison James P.
Published: April 2023

Pmel-1 dynamics in TDLN subsequent to injection of α-H2-Db antibodies.
Suppl Movie 7 from Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility
Authors: Pentcheva-Hoang Tsvetelina , Simpson Tyler R. , Montalvo-Ortiz Welby , Allison James P.
Published: April 2023

Pmel-1 dynamics in TDLN prior to injection of α-H2-Db antibodies.
Suppl Movie 2 from Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility
Authors: Pentcheva-Hoang Tsvetelina , Simpson Tyler R. , Montalvo-Ortiz Welby , Allison James P.
Published: April 2023

Pmel-1 dynamics in tumors subsequent to acute CTLA-4 blockade.
Suppl Movie 14 from Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility
Authors: Pentcheva-Hoang Tsvetelina , Simpson Tyler R. , Montalvo-Ortiz Welby , Allison James P.
Published: April 2023

Pmel-1 dynamics in TDLN subsequent to injection of α-CTLA-4 Fab fragments.
Suppl Movie 12 from Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility
Authors: Pentcheva-Hoang Tsvetelina , Simpson Tyler R. , Montalvo-Ortiz Welby , Allison James P.
Published: April 2023

Pmel-1 dynamics in TDLN subsequent to injection of hamster Ig.
Supplementary Table 2 from Epigenetic Potentiation of NY-ESO-1 Vaccine Therapy in Human Ovarian Cancer
Authors: Odunsi Kunle , Matsuzaki Junko , James Smitha R. , Mhawech-Fauceglia Paulette , Tsuji Takemasa , Miller Austin , Zhang Wa , Akers Stacey N. , Griffiths Elizabeth A. , Miliotto Anthony , Beck Amy , Batt Carl A. , Ritter Gerd , Lele Shashikant , Gnjatic Sacha , Karpf Adam R.
Published: April 2023

PDF file - 45K, Table S2. Adverse events observed in the clinical trial.
Supplementary Figure Legend from Combining Oncolytic HSV-1 with Immunogenic Cell Death-Inducing Drug Mitoxantrone Breaks Cancer Immune Tolerance and Improves Therapeutic Efficacy
Authors: Workenhe Samuel T. , Pol Jonathan G. , Lichty Brian D. , Cummings Derek T. , Mossman Karen L.
Published: April 2023

PDF file - 75K
Supplementary Methods, Figures 1 - 4, Tables 1 - 2 from Chronic Lymphocytic Leukemia Monitoring with a Lamprey Idiotope-Specific Antibody
Authors: Nakahara Hirotomo , Herrin Brantley R. , Alder Matthew N. , Catera Rosa , Yan Xiao-Jie , Chiorazzi Nicholas , Cooper Max D.
Published: April 2023

PDF file - 192K, Figure S1: Flow cytometric analysis of monoclonal VLR39 reactivity with different cell types and cell lines. Figure S2: Flow cytometric analysis of monoclonal VLR39 reactivity with CLL cells with different VH gene sets. Figure S3: CLL VH gene sequence analysis. Figure S4: IGHV-D-J sequence alignment of VLR39 sorted cells. Table S1: CLL VH gene families and HCDR3 sequences. Table S2: Detection of CLL recurrence by quantitative real-time
Supplementary Figure Legend from Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells
Authors: Selby Mark J. , Engelhardt John J. , Quigley Michael , Henning Karla A. , Chen Timothy , Srinivasan Mohan , Korman Alan J.
Published: April 2023

PDF file - 102K
Supplementary Figures 1 - 4 from JAK2 Expression Is Associated with Tumor-Infiltrating Lymphocytes and Improved Breast Cancer Outcomes: Implications for Evaluating JAK2 Inhibitors
Authors: Miller Chris P. , Thorpe Jason D. , Kortum Amanda N. , Coy Catherine M. , Cheng Wei-Yi , Yang Tai-Hsien Ou , Anastassiou Dimitris , Beatty J. David , Urban Nicole D. , Blau C. Anthony
Published: April 2023

PDF file - 188K, Supplementary Figure S1. JAK2 mRNA quantification in primary breast tumors. Supplementary Figure S2. Evaluating JAK2 mRNA and protein levels in human breast cancer cell lines. Supplementary Figure S3. Validating the specificity of a total JAK2 antibody for immunohistochemistry. Supplementary Figure S4. Ruxolitinib inhibits the anti-CD3-dependent production of IFN-gamma.
Supplementary Table 4 from Locally Delivered CD40 Agonist Antibody Accumulates in Secondary Lymphoid Organs and Eradicates Experimental Disseminated Bladder Cancer
Authors: Sandin Linda C. , Orlova Anna , Gustafsson Erika , Ellmark Peter , Tolmachev Vladimir , Tötterman Thomas H. , Mangsbo Sara M.
Published: April 2023

PDF file - 67K, Table 4: In vivo biodistribution 72h (also see Supplementary Fig. S3B). Statistical differences calculated between anti-CD40 and rat IgG2a and the two administration routes (n=3-4, Student?s paired t-test).
Figure S9 from Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases
Authors: Magee Michael S. , Abraham Tara S. , Baybutt Trevor R. , Flickinger John C. , Ridge Natalie A. , Marszalowicz Glen P. , Prajapati Priyanka , Hersperger Adam R. , Waldman Scott A. , Snook Adam E.
Published: April 2023

Figure S9 shows that 5F9.m28BBz CAR-T cells do not kill hGUCY2C-deficient human colorectal cancer cells.
Supplementary Figure 3 from Role of Crosslinking for Agonistic CD40 Monoclonal Antibodies as Immune Therapy of Cancer
Authors: Richman Lee P. , Vonderheide Robert H.
Published: April 2023

PDF file - 82K, Supplementary Figure 3. CD40 antibody fine specificity.
Supplementary Figures 1 and 2 from Ipilimumab Treatment Results in an Early Decrease in the Frequency of Circulating Granulocytic Myeloid-Derived Suppressor Cells as well as Their Arginase1 Production
Authors: de Coaña Yago Pico , Poschke Isabel , Gentilcore Giusy , Mao Yumeng , Nyström Maria , Hansson Johan , Masucci Giuseppe V. , Kiessling Rolf
Published: April 2023

PDF file - 75K, Supplementary figure 1 depicts the absolute lymphocyte counts in patients during ipilimumab treatment. Supplementary figure 2 depicts the correlation analysis of different dellular populations
Data Supplement from Downregulation of MHC-I Expression Is Prevalent but Reversible in Merkel Cell Carcinoma
Authors: Paulson Kelly G. , Tegeder Andrew , Willmes Christoph , Iyer Jayasri G. , Afanasiev Olga K. , Schrama David , Koba Shinichi , Thibodeau Renee , Nagase Kotaro , Simonson William T. , Seo Aaron , Koelle David M. , Madeleine Margaret , Bhatia Shailender , Nakajima Hideki , Sano Shigetoshi , Hardwick James S. , Disis Mary L. , Cleary Michele A. , Becker Jürgen C. , Nghiem Paul
Published: April 2023

Allred proportion (ranging from 0-5) and intensity (ranging from 0-3) scores for each tumor. The median score among triplicate TMA cores and reviewers was utilized. Most MCC tumors with an Allred score of 7 continued to express MHC class I in all tumor cells, however the intensity of expression was significantly reduced as compared to those with an Allred score of 8.
Supplementary Figures 3 - 4 from mTOR Inhibition Improves Antitumor Effects of Vaccination with Antigen-Encoding RNA
Authors: Diken Mustafa , Kreiter Sebastian , Vascotto Fulvia , Selmi Abderraouf , Attig Sebastian , Diekmann Jan , Huber Christoph , Türeci Özlem , Sahin Ugur
Published: April 2023

PDF file - 1350K, Description of effects of Rapamycin on blood hematogram values and on frequencies of antigen specific T cells.
Supplementary Figure 4 from Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines
Authors: Farsaci Benedetto , Donahue Renee N. , Coplin Michael A. , Grenga Italia , Lepone Lauren M. , Molinolo Alfredo A. , Hodge James W.
Published: April 2023

Sunitinib alone or in combination with vaccine decreased the frequency of splenic MDSCs and monocytes in tumor bearing mice.
Supplementary Figure 1 from Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines
Authors: Farsaci Benedetto , Donahue Renee N. , Coplin Michael A. , Grenga Italia , Lepone Lauren M. , Molinolo Alfredo A. , Hodge James W.
Published: April 2023

Sunitinib or sorafenib in combination with rMVA-Twist- TRICOM vaccine decreased tumor burden and vascular area in the 4T1 breast cancer model.
Data Supplement from Quantitative Effect of Natural Killer–Cell Licensing on Hepatocellular Carcinoma Recurrence after Curative Hepatectomy
Authors: Tanimine Naoki , Tanaka Yuka , Kobayashi Tsuyoshi , Tashiro Hirotaka , Miki Daiki , Imamura Michio , Aikata Hiroshi , Tanaka Junko , Chayama Kazuaki , Ohdan Hideki
Published: April 2023

(A) According to TNM stages, Kaplan-Meier analyses of the 5-year cumulative recurrence risk were performed for the 138 matched patients belonging to the highly and poorly licensed NK groups. Further subgroup analyses were performed for patients with (B) stage I, (C) stage II, and (D) stage IIIA HCC.
Data Supplement from Quantitative Effect of Natural Killer–Cell Licensing on Hepatocellular Carcinoma Recurrence after Curative Hepatectomy
Authors: Tanimine Naoki , Tanaka Yuka , Kobayashi Tsuyoshi , Tashiro Hirotaka , Miki Daiki , Imamura Michio , Aikata Hiroshi , Tanaka Junko , Chayama Kazuaki , Ohdan Hideki
Published: April 2023

Cumulative risk of recurrence and overall survival were compared by log-rank test for univariate analyses. The Cox proportional hazards regression model was performed for multivariate survival analysis. Only variables yielding P < 0.1 in the univariate analysis were included in the multivariate model.