bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative
Authors: Aftimos Philippe , Oliveira Mafalda , Irrthum Alexandre , Fumagalli Debora , Sotiriou Christos , Gal-Yam Einav Nili , Robson Mark E. , Ndozeng Justin , Di Leo Angelo , Ciruelos Eva M. , de Azambuja Evandro , Viale Giuseppe , Scheepers Elsemieke D. , Curigliano Giuseppe , Bliss Judith M. , Reis-Filho Jorge S. , Colleoni Marco , Balic Marija , Cardoso Fatima , Albanell Joan , Duhem Caroline , Marreaud Sandrine , Romagnoli Dario , Rojas Beatriz , Gombos Andrea , Wildiers Hans , Guerrero-Zotano Angel , Hall Peter , Bonetti Andrea , Larsson Karolina Fs , Degiorgis Martina , Khodaverdi Silvia , Greil Richard , Sverrisdóttir Ásgerdur , Paoli Marta , Seyll Ethel , Loibl Sibylle , Linderholm Barbro , Zoppoli Gabriele , Davidson Nancy E. , Johannsson Oskar Th , Bedard Philippe L. , Loi Sherene , Knox Susan , Cameron David A. , Harbeck Nadia , Montoya Maite Lasa , Brandão Mariana , Vingiani Andrea , Caballero Carmela , Hilbers Florentine S. , Yates Lucy R. , Benelli Matteo , Venet David , Piccart Martine J.
Published: April 2023

Abstract
AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2− cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC.
Significance:
The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.

This article is highlighted in the In This Issue feature, p. 2659
Data from Intracellular Cholesterol Pools Regulate Oncogenic Signaling and Epigenetic Circuitries in Early T-cell Precursor Acute Lymphoblastic Leukemia
Authors: Rashkovan Marissa , Albero Robert , Gianni Francesca , Perez-Duran Pablo , Miller Hannah I. , Mackey Adam L. , Paietta Elisabeth M. , Tallman Martin S. , Rowe Jacob M. , Litzow Mark R. , Wiernik Peter H. , Luger Selina , Sulis Maria Luisa , Soni Rajesh K. , Ferrando Adolfo A.
Published: April 2023

Abstract
Early T-cell acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematologic malignancy associated with early relapse and poor prognosis that is genetically, immunophenotypically, and transcriptionally distinct from more mature T-cell acute lymphoblastic leukemia (T-ALL) tumors. Here, we leveraged global metabolomic and transcriptomic profiling of primary ETP- and T-ALL leukemia samples to identify specific metabolic circuitries differentially active in this high-risk leukemia group. ETP-ALLs showed increased biosynthesis of phospholipids and sphingolipids and were specifically sensitive to inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in the mevalonate pathway. Mechanistically, inhibition of cholesterol synthesis inhibited oncogenic AKT1 signaling and suppressed MYC expression via loss of chromatin accessibility at a leukemia stem cell–specific long-range MYC enhancer. In all, these results identify the mevalonate pathway as a druggable novel vulnerability in high-risk ETP-ALL cells and uncover an unanticipated critical role for cholesterol biosynthesis in signal transduction and epigenetic circuitries driving leukemia cell growth and survival.
Significance:
Overtly distinct cell metabolic pathways operate in ETP- and T-ALL pointing to specific metabolic vulnerabilities. Inhibition of mevalonate biosynthesis selectively blocks oncogenic AKT–MYC signaling in ETP-ALL and suppresses leukemia cell growth. Ultimately, these results will inform the development of novel tailored and more effective treatments for patients with high-risk ETP-ALL.

This article is highlighted in the In This Issue feature, p. 587
Data from Independent Drug Action in Combination Therapy: Implications for Precision Oncology
Authors: Plana Deborah , Palmer Adam C. , Sorger Peter K.
Published: April 2023

Abstract
Combination therapies are superior to monotherapy for many cancers. This advantage was historically ascribed to the ability of combinations to address tumor heterogeneity, but synergistic interaction is now a common explanation as well as a design criterion for new combinations. We review evidence that independent drug action, described in 1961, explains the efficacy of many practice-changing combination therapies: it provides populations of patients with heterogeneous drug sensitivities multiple chances of benefit from at least one drug. Understanding response heterogeneity could reveal predictive or pharmacodynamic biomarkers for more precise use of existing drugs and realize the benefits of additivity or synergy.
Significance:
The model of independent drug action represents an effective means to predict the magnitude of benefit likely to be observed in new clinical trials for combination therapies. The “bet-hedging” strategy implicit in independent action suggests that individual patients often benefit from only a subset—sometimes one—of the drugs in a combination. Personalized, targeted combination therapy, consisting of agents likely to be active in a particular patient, will increase, perhaps substantially, the magnitude of therapeutic benefit. Precision approaches of this type will require a better understanding of variability in drug response and new biomarkers, which will entail preclinical research on diverse panels of cancer models rather than studying drug synergy in unusually sensitive models.
Data from Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms
Authors: Bertrums Eline J.M. , Rosendahl Huber Axel K.M. , de Kanter Jurrian K. , Brandsma Arianne M. , van Leeuwen Anaïs J.C.N. , Verheul Mark , van den Heuvel-Eibrink Marry M. , Oka Rurika , van Roosmalen Markus J. , de Groot-Kruseman Hester A. , Zwaan C. Michel , Goemans Bianca F. , van Boxtel Ruben
Published: April 2023

Abstract
Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPC) before and after cancer treatment of 24 children. Of these children, 19 developed therapy-related myeloid neoplasms (t-MN). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure.
Significance:
Our study shows that chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, whereas in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging.

This article is highlighted in the In This Issue feature, p. 1825
Data from Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence
Authors: Linder Simon , Hoogstraat Marlous , Stelloo Suzan , Eickhoff Nils , Schuurman Karianne , de Barros Hilda , Alkemade Maartje , Bekers Elise M. , Severson Tesa M. , Sanders Joyce , Huang Chia-Chi Flora , Morova Tunc , Altintas Umut Berkay , Hoekman Liesbeth , Kim Yongsoo , Baca Sylvan C. , Sjöström Martin , Zaalberg Anniek , Hintzen Dorine C. , de Jong Jeroen , Kluin Roelof J.C. , de Rink Iris , Giambartolomei Claudia , Seo Ji-Heui , Pasaniuc Bogdan , Altelaar Maarten , Medema René H. , Feng Felix Y. , Zoubeidi Amina , Freedman Matthew L. , Wessels Lodewyk F.A. , Butler Lisa M. , Lack Nathan A. , van der Poel Henk , Bergman Andries M. , Zwart Wilbert
Published: April 2023

Abstract
In prostate cancer, androgen receptor (AR)–targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients’ clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.
Significance:
Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development.

See related commentary by Zhang et al., p. 2017.

This article is highlighted in the In This Issue feature, p. 2007
Data from Mesenchymal Lineage Heterogeneity Underlies Nonredundant Functions of Pancreatic Cancer–Associated Fibroblasts
Authors: Helms Erin J. , Berry Mark W. , Chaw R. Crystal , DuFort Christopher C. , Sun Duanchen , Onate M. Kathrina , Oon Chet , Bhattacharyya Sohinee , Sanford-Crane Hannah , Horton Wesley , Finan Jennifer M. , Sattler Ariana , Makar Rosemary , Dawson David W. , Xia Zheng , Hingorani Sunil R. , Sherman Mara H.
Published: April 2023

Abstract
Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSC), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed nonredundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs and demonstrate unique functions for CAFs of a defined cellular origin.
Significance:
By tracking and ablating a specific CAF population, we find that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity and signaling gradients diversify PDAC CAFs.

See related commentary by Cukierman, p. 296.

This article is highlighted in the In This Issue feature, p. 275
Data from EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma
Authors: Durbin Adam D. , Wang Tingjian , Wimalasena Virangika K. , Zimmerman Mark W. , Li Deyao , Dharia Neekesh V. , Mariani Luca , Shendy Noha A.M. , Nance Stephanie , Patel Anand G. , Shao Ying , Mundada Maya , Maxham Lily , Park Paul M.C. , Sigua Logan H. , Morita Ken , Conway Amy Saur , Robichaud Amanda L. , Perez-Atayde Antonio R. , Bikowitz Melissa J. , Quinn Taylor R. , Wiest Olaf , Easton John , Schönbrunn Ernst , Bulyk Martha L. , Abraham Brian J. , Stegmaier Kimberly , Look A. Thomas , Qi Jun
Published: April 2023

Abstract
Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed “JQAD1” that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Furthermore, JQAD1 activity is critically determined by cereblon (CRBN) expression across NB cells.
Significance:
EP300, but not CBP, controls oncogenic CRC-driven transcription in high-risk NB by binding TFAP2β. We developed JQAD1, a CRBN-dependent PROTAC degrader with preferential activity against EP300 and demonstrated its activity in NB. JQAD1 has limited toxicity to untransformed cells and is effective in vivo in a CRBN-dependent manner.

This article is highlighted in the In This Issue feature, p. 587
Data from IL27 Signaling Serves as an Immunologic Checkpoint for Innate Cytotoxic Cells to Promote Hepatocellular Carcinoma
Authors: Aghayev Turan , Mazitova Aleksandra M. , Fang Jennifer R. , Peshkova Iuliia O. , Rausch Matthew , Hung Manhsin , White Kerry F. , Masia Ricard , Titerina Elizaveta K. , Fatkhullina Aliia R. , Cousineau Isabelle , Turcotte Simon , Zhigarev Dmitry , Marchenko Anastasiia , Khoziainova Svetlana , Makhov Petr , Tan Yin Fei , Kossenkov Andrew V. , Wiest David L. , Stagg John , Wang Xin Wei , Campbell Kerry S. , Dzutsev Amiran K. , Trinchieri Giorgio , Hill Jonathan A. , Grivennikov Sergei I. , Koltsova Ekaterina K.
Published: April 2023

Abstract
Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig­naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC.
Significance:
HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease.

This article is highlighted in the In This Issue feature, p. 1825
Data from Modulation of BCL-2 in Both T Cells and Tumor Cells to Enhance Chimeric Antigen Receptor T-cell Immunotherapy against Cancer
Authors: Lee Yong Gu , Guruprasad Puneeth , Ghilardi Guido , Pajarillo Raymone , Sauter Christopher Tor , Patel Ruchi , Ballard Hatcher J. , Hong Seok Jae , Chun Inkook , Yang Nicholas , Amelsberg Kimberly V. , Cummins Katherine D. , Svoboda Jakub , Gill Saar , Chong Elise A. , North Khrystyna , Church Sarah E. , Fraietta Joseph A. , Chang Wan-Jung , Lacey Simon F. , Lu Xueqing Maggie , Zhang Yunlin , Whig Kanupriya , Schultz David C. , Cherry Sara , Gerson James , Schuster Stephen J. , Porazzi Patrizia , Ruella Marco
Published: April 2023

Abstract
Chimeric antigen receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two thirds of patients experience treatment failure. Resistance to apoptosis is a key feature of cancer cells, and it is associated with treatment failure. In 87 patients with NHL treated with anti-CD19 CART, we found that chromosomal alteration of B-cell lymphoma 2 (BCL-2), a critical antiapoptotic regulator, in lymphoma cells was associated with reduced survival. Therefore, we combined CART19 with the FDA-approved BCL-2 inhibitor venetoclax and demonstrated in vivo synergy in venetoclax-sensitive NHL. However, higher venetoclax doses needed for venetoclax-resistant lymphomas resulted in CART toxicity. To overcome this limitation, we developed venetoclax-resistant CART by overexpressing mutated BCL-2(F104L), which is not recognized by venetoclax. Notably, BCL-2(F104L)-CART19 synergized with venetoclax in multiple lymphoma xenograft models. Furthermore, we uncovered that BCL-2 overexpression in T cells intrinsically enhanced CART antitumor activity in preclinical models and in patients by prolonging CART persistence.
Significance:
This study highlights the role of BCL-2 in resistance to CART immunotherapy for cancer and introduces a novel concept for combination therapies—the engineering of CART cells to make them resistant to proapoptotic small molecules, thereby enhancing the therapeutic index of these combination therapies.

This article is highlighted in the In This Issue feature, p. 2221
Data from A Therapeutically Actionable Protumoral Axis of Cytokines Involving IL-8, TNFα, and IL-1β
Authors: Olivera Irene , Sanz-Pamplona Rebeca , Bolaños Elixabet , Rodriguez Inmaculada , Etxeberria Iñaki , Cirella Assunta , Egea Josune , Garasa Saray , Migueliz Itziar , Eguren-Santamaria Iñaki , Sanmamed Miguel F. , Glez-Vaz Javier , Azpilikueta Arantza , Alvarez Maite , Ochoa María C. , Malacrida Beatrice , Propper David , de Andrea Carlos E. , Berraondo Pedro , Balkwill Frances R. , Teijeira Álvaro , Melero Ignacio
Published: April 2023

Abstract
Interleukin-8 (CXCL8) produced in the tumor microenvironment correlates with poor response to checkpoint inhibitors and is known to chemoattract and activate immunosuppressive myeloid leukocytes. In human cancer, IL8 mRNA levels correlate with IL1B and TNF transcripts. Both cytokines induced IL-8 functional expression from a broad variety of human cancer cell lines, primary colon carcinoma organoids, and fresh human tumor explants. Although IL8 is absent from the mouse genome, a similar murine axis in which TNFα and IL-1β upregulate CXCL1 and CXCL2 in tumor cells was revealed. Furthermore, intratumoral injection of TNFα and IL-1β induced IL-8 release from human malignant cells xenografted in immunodeficient mice. In all these cases, the clinically used TNFα blockers infliximab and etanercept or the IL-1β inhibitor anakinra was able to interfere with this pathogenic cytokine loop. Finally, in paired plasma samples of patients with cancer undergoing TNFα blockade with infliximab in a clinical trial, reductions of circulating IL-8 were substantiated.
Significance:
IL-8 attracts immunosuppressive protumor myeloid cells to the tumor microenvironment, and IL-8 levels correlate with poor response to checkpoint inhibitors. TNFα and IL-1β are identified as major inducers of IL-8 expression on malignant cells across cancer types and models in a manner that is druggable with clinically available neutralizing agents.

This article is highlighted in the In This Issue feature, p. 2007
Data from DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition
Authors: Izquierdo Elisa , Carvalho Diana M. , Mackay Alan , Temelso Sara , Boult Jessica K.R. , Pericoli Giulia , Fernandez Elisabet , Das Molina , Molinari Valeria , Grabovska Yura , Rogers Rebecca F. , Ajmone-Cat Maria Antonietta , Proszek Paula Z. , Stubbs Mark , Depani Sarita , O'Hare Patricia , Yu Lu , Roumelioti Georgia , Choudhary Jyoti S. , Clarke Matthew , Fairchild Amy R. , Jacques Thomas S. , Grundy Richard G. , Howell Lisa , Picton Susan , Adamski Jenny , Wilson Shaun , Gray Juliet C. , Zebian Bassel , Marshall Lynley V. , Carceller Fernando , Grill Jacques , Vinci Maria , Robinson Simon P. , Hubank Michael , Hargrave Darren , Jones Chris
Published: April 2023

Abstract
The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation.
Significance:
We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic.

This article is highlighted in the In This Issue feature, p. 587
Data from AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer
Authors: Noronha Ashish , Belugali Nataraj Nishanth , Lee Joo Sang , Zhitomirsky Benny , Oren Yaara , Oster Sara , Lindzen Moshit , Mukherjee Saptaparna , Will Rainer , Ghosh Soma , Simoni-Nieves Arturo , Verma Aakanksha , Chatterjee Rishita , Borgoni Simone , Robinson Welles , Sinha Sanju , Brandis Alexander , Kerr D. Lucas , Wu Wei , Sekar Arunachalam , Giri Suvendu , Chung Youngmin , Drago-Garcia Diana , Danysh Brian P. , Lauriola Mattia , Fiorentino Michelangelo , Ardizzoni Andrea , Oren Moshe , Blakely Collin M. , Ezike Jideofor , Wiemann Stefan , Parida Laxmi , Bivona Trever G. , Aqeilan Rami I. , Brugge Joan S. , Regev Aviv , Getz Gad , Ruppin Eytan , Yarden Yosef
Published: April 2023

Abstract
Anticancer therapies have been limited by the emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error-prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether the treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease, we observed upregulation of GAS6, whereas ablation of GAS6's receptor, AXL, eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC, and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators.
Significance:
EGFR-mutant lung cancers treated with kinase inhibitors often evolve resistance due to secondary mutations. We report that in similarity to the bacterial SOS response stimulated by antibiotics, endogenous mutators are activated in drug-treated cells, and this heralds tolerance. Blocking the process prevented resistance in xenograft models, which offers new treatment strategies.

This article is highlighted in the In This Issue feature, p. 2483
Data from African Ancestry–Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent
Authors: Martini Rachel , Delpe Princesca , Chu Timothy R. , Arora Kanika , Lord Brittany , Verma Akanksha , Bedi Deepa , Karanam Balasubramanyam , Elhussin Isra , Chen Yalei , Gebregzabher Endale , Oppong Joseph K. , Adjei Ernest K. , Jibril Suleiman Aisha , Awuah Baffour , Muleta Mahteme Bekele , Abebe Engida , Kyei Ishmael , Aitpillah Frances S. , Adinku Michael O. , Ankomah Kwasi , Osei-Bonsu Ernest Baawuah , Chitale Dhananjay A. , Bensenhaver Jessica M. , Nathanson David S. , Jackson LaToya , Petersen Lindsay F. , Proctor Erica , Stonaker Brian , Gyan Kofi K. , Gibbs Lee D. , Monojlovic Zarko , Kittles Rick A. , White Jason , Yates Clayton C. , Manne Upender , Gardner Kevin , Mongan Nigel , Cheng Esther , Ginter Paula , Hoda Syed , Elemento Olivier , Robine Nicolas , Sboner Andrea , Carpten John D. , Newman Lisa , Davis Melissa B.
Published: April 2023

Abstract
Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent.
Significance:
Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race–group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort.

See related commentary by Hamilton et al., p. 2496.

This article is highlighted in the In This Issue feature, p. 2483
Data from Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation
Authors: Chen Sisi , Vedula Rahul S. , Cuevas-Navarro Antonio , Lu Bin , Hogg Simon J. , Wang Eric , Benbarche Salima , Knorr Katherine , Kim Won Jun , Stanley Robert F. , Cho Hana , Erickson Caroline , Singer Michael , Cui Dan , Tittley Steven , Durham Benjamin H. , Pavletich Tatiana S. , Fiala Elise , Walsh Michael F. , Inoue Daichi , Monette Sebastien , Taylor Justin , Rosen Neal , McCormick Frank , Lindsley R. Coleman , Castel Pau , Abdel-Wahab Omar
Published: April 2023

Abstract
Recently, screens for mediators of resistance to FLT3 and ABL kinase inhibitors in leukemia resulted in the discovery of LZTR1 as an adapter of a Cullin-3 RING E3 ubiquitin ligase complex responsible for the degradation of RAS GTPases. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations was identified in clonal hematopoietic conditions. Here we identify that loss of LZTR1, or leukemia-associated mutants in the LZTR1 substrate and RAS GTPase RIT1 that escape degradation, drives hematopoietic stem cell (HSC) expansion and leukemia in vivo. Although RIT1 stabilization was sufficient to drive hematopoietic transformation, transformation mediated by LZTR1 loss required MRAS. Proteolysis targeting chimeras (PROTAC) against RAS or reduction of GTP-loaded RAS overcomes LZTR1 loss-mediated resistance to FLT3 inhibitors. These data reveal proteolysis of noncanonical RAS proteins as novel regulators of HSC self-renewal, define the function of RIT1 and LZTR1 mutations in leukemia, and identify means to overcome drug resistance due to LZTR1 downregulation.
Significance:
Here we identify that impairing proteolysis of the noncanonical RAS GTPases RIT1 and MRAS via LZTR1 downregulation or leukemia-associated mutations stabilizing RIT1 enhances MAP kinase activation and drives leukemogenesis. Reducing the abundance of GTP-bound KRAS and NRAS overcomes the resistance to FLT3 kinase inhibitors associated with LZTR1 downregulation in leukemia.

This article is highlighted in the In This Issue feature, p. 2221
Data from An Aged/Autoimmune B-cell Program Defines the Early Transformation of Extranodal Lymphomas
Authors: Venturutti Leandro , Rivas Martin A. , Pelzer Benedikt W. , Flümann Ruth , Hansen Julia , Karagiannidis Ioannis , Xia Min , McNally Dylan R. , Isshiki Yusuke , Lytle Andrew , Teater Matt , Chin Christopher R. , Meydan Cem , Knittel Gero , Ricker Edd , Mason Christopher E. , Ye Xiaofei , Pan-Hammarström Qiang , Steidl Christian , Scott David W. , Reinhardt Hans Christian , Pernis Alessandra B. , Béguelin Wendy , Melnick Ari M.
Published: April 2023

Abstract
A third of patients with diffuse large B-cell lymphoma (DLBCL) present with extranodal dissemination, which is associated with inferior clinical outcomes. MYD88L265P is a hallmark extranodal DLBCL mutation that supports lymphoma proliferation. Yet extranodal lymphomagenesis and the role of MYD88L265P in transformation remain mostly unknown. Here, we show that B cells expressing Myd88L252P (MYD88L265P murine equivalent) activate, proliferate, and differentiate with minimal T-cell costimulation. Additionally, Myd88L252P skewed B cells toward memory fate. Unexpectedly, the transcriptional and phenotypic profiles of B cells expressing Myd88L252P, or other extranodal lymphoma founder mutations, resembled those of CD11c+T-BET+ aged/autoimmune memory B cells (AiBC). AiBC-like cells progressively accumulated in animals prone to develop lymphomas, and ablation of T-BET, the AiBC master regulator, stripped mouse and human mutant B cells of their competitive fitness. By identifying a phenotypically defined prospective lymphoma precursor population and its dependencies, our findings pave the way for the early detection of premalignant states and targeted prophylactic interventions in high-risk patients.
Significance:
Extranodal lymphomas feature a very poor prognosis. The identification of phenotypically distinguishable prospective precursor cells represents a milestone in the pursuit of earlier diagnosis, patient stratification, and prophylactic interventions. Conceptually, we found that extranodal lymphomas and autoimmune disorders harness overlapping pathogenic trajectories, suggesting these B-cell disorders develop and evolve within a spectrum.

See related commentary by Leveille et al. (Blood Cancer Discov 2023;4:8–11).

This article is highlighted in the In This Issue feature, p. 1
Data from A Ubiquitination Cascade Regulating the Integrated Stress Response and Survival in Carcinomas
Authors: Cervia Lisa D. , Shibue Tsukasa , Borah Ashir A. , Gaeta Benjamin , He Linh , Leung Lisa , Li Naomi , Moyer Sydney M. , Shim Brian H. , Dumont Nancy , Gonzalez Alfredo , Bick Nolan R. , Kazachkova Mariya , Dempster Joshua M. , Krill-Burger John Michael , Piccioni Federica , Udeshi Namrata D. , Olive Meagan E. , Carr Steven A. , Root David E. , McFarland James M. , Vazquez Francisca , Hahn William C.
Published: April 2023

Abstract
Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 cancer cell lines to identify selective coessentiality modules and found that a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1, and UBR4 is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor, a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy.
Significance:
We describe the identification of a heretofore unrecognized ubiquitin ligase complex that prevents the aberrant activation of the ISR in a subset of cancer cells. This provides a novel insight on the regulation of ISR and exposes a therapeutic opportunity to selectively eliminate these cancer cells.

See related commentary Leli and Koumenis, p. 535.

This article is highlighted in the In This Issue feature, p. 517
Data from Discovery of Targets for Immune–Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha
Authors: Sahu Avinash , Wang Xiaoman , Munson Phillip , Klomp Jan P.G. , Wang Xiaoqing , Gu Shengqing Stan , Han Ya , Qian Gege , Nicol Phillip , Zeng Zexian , Wang Chenfei , Tokheim Collin , Zhang Wubing , Fu Jingxin , Wang Jin , Nair Nishanth Ulhas , Rens Joost A.P. , Bourajjaj Meriem , Jansen Bas , Leenders Inge , Lemmers Jaap , Musters Mark , van Zanten Sanne , van Zelst Laura , Worthington Jenny , Liu Jun S. , Juric Dejan , Meyer Clifford A. , Oubrie Arthur , Liu X. Shirley , Fisher David E. , Flaherty Keith T.
Published: April 2023

Abstract
Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell–specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway and then used it to identify 38 candidate immune–metabolic regulators. We show the tumor activities of these regulators stratify patients with melanoma by their response to anti–PD-1 using machine learning and deep neural approaches, which improve the predictive power of current biomarkers. The topmost identified regulator, ESRRA, is activated in immunotherapy-resistant tumors. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization, and (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth suppressor evasion pathways. BipotentR (http://bipotentr.dfci.harvard.edu/) provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms.
Significance:
BipotentR presents resources for evaluating patient response and identifying targets for drugs that can kill tumors through multiple mechanisms concurrently. Inhibition of the topmost candidate target killed tumors by suppressing energy metabolism and effects on two immune mechanisms.

This article is highlighted in the In This Issue feature, p. 517
Supplementary Figure 3 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 - 135K, Supplementary Figure 3. Effectiveness of NK cell depletion.
Supplementary Figures from Collapse of the Plasmacytoid Dendritic Cell Compartment in Advanced Cutaneous Melanomas by Components of the Tumor Cell Secretome
Authors: Vescovi Raffaella , Monti Matilde , Moratto Daniele , Paolini Lucia , Consoli Francesca , Benerini Luisa , Melocchi Laura , Calza Stefano , Chiudinelli Mariella , Rossi Giulio , Bugatti Mattia , Maio Michele , Fonsatti Ester , Farisoglio Camillo , Simbolo Michele , Almici Camillo , Verardi Rosanna , Scarpa Aldo , Bergese Paolo , Manganoni Ausilia , Facchetti Fabio , Vermi William
Published: April 2023

Supplementary Figures
Supplementary Table S2 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

Toxicities.
Supplementary Table S1 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

Peptide candidates used for personalized peptide vaccination.
Suppl Movie 6 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-B7-1 and α-B7-2 antibodies.
Supplementary Table 1 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 - 41K, Table S1. Characteristics of patients enrolled in the clinical trial.
Supplementary Figure Legends 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 - 59K
Supplementary Figure 2 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 - 463K, Supplementary figure 2. Percent survival and fold changes in tumor volume after treatment with KM100 and/or 1 microM MTX
Supplementary File from Autoantibody Development under Treatment with Immune-Checkpoint Inhibitors
Authors: de Moel Emma C. , Rozeman Elisa A. , Kapiteijn Ellen H. , Verdegaal Els M.E. , Grummels Annette , Bakker Jaap A. , Huizinga Tom W.J. , Haanen John B. , Toes René E.M. , van der Woude Diane
Published: April 2023

Supplementary Figure S1 Supplementary Figure S2 Supplementary Table S1 Supplementary Table S2
Supplementary Figure Legends 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 - 32K
Supplementary Figure 1 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 - 278K, Figure 1. Local low-dose anti-CD40 therapy generates distant anti-tumor effects and inhibits B16 tumor growth.
Figure S6 from Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation
Authors: Hartley Genevieve P. , Chow Lyndah , Ammons Dylan T. , Wheat William H. , Dow Steven W.
Published: April 2023

Supplemental Figure S6. Ingenuity Pathway Analysis revealed altered cell signaling pathways in PD-L1 antibody-treated macrophages consistent with changes observed in both in vitro and in vivo studies. Macrophages were treated with medium only, irrelevant isotype antibody, or PD-L1 antibody for 24 hours prior to RNA extraction for RNA sequencing analysis. Ingenuity Pathway Analysis was used to identify altered signaling pathways, of which included (A) Type I Diabetes Mellitus (B) LXR/RXR activation, (C) PPAR signaling, (D) TNFR2 signaling (E) Apoptosis signaling, and (F) Calcium-induced T lymphocyte apoptosis signaling. The key is as follows: red is upregulated, and green is downregulated. These data were generated using macrophages from 9 mice, with 3 mice in each treatment group.
Figure S5 from Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation
Authors: Hartley Genevieve P. , Chow Lyndah , Ammons Dylan T. , Wheat William H. , Dow Steven W.
Published: April 2023

Supplemental Figure S5. LPS stimulation of macrophages fails to promote macrophage survival or morphological changes. Macrophages were incubated with medium only, irrelevant isotype antibody, irrelevant isotype antibody + LPS, or PD-L1 antibody. After 6 days, images of the macrophages were taken (A). Changes in well confluence were measured every 3 hours for 6 days with an IncuCyte ZOOM live cell imaging system (B), and an MTT was performed to measure survival of the cells after the 6 days. Mean absorbances of MTT substrate were compared statistically with one-way ANOVA and Prism7 software (C), with statistically significant differences denoted as P-value *** < 0.0005. Similar results were obtained in 2 independent experiments.
Figure S3 from Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation
Authors: Hartley Genevieve P. , Chow Lyndah , Ammons Dylan T. , Wheat William H. , Dow Steven W.
Published: April 2023

Supplemental Figure S3. Morphology of macrophages treated with control antibodies. Macrophages were incubated with medium only, irrelevant isotype antibody, a macrophage-specific antibody (CD11b), Fc-blocking antibody, or pre-treated with Fc-blocking antibody for 1 hour before treatment with PD-L1 antibody. Photographs of the macrophages were taken after 48 hours with a confocal microscope.
Figure S1 from Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation
Authors: Hartley Genevieve P. , Chow Lyndah , Ammons Dylan T. , Wheat William H. , Dow Steven W.
Published: April 2023

Supplemental Figure S1. PD-L1, PD-1, and CD80 expression by bone marrow-derived macrophages. Bone marrow monocytes were cultured with M-CSF for one week for the enrichment of macrophages and plated for adherent culture overnight. They were then detached and processed for flow cytometric analysis of PD-L1 (A), PD-1 (B), and CD80 (C) expression. Histograms are shown in where isotype stain = gray filled and solid line = cultured macrophages.
Supplementary Figure 2 from Peptide Vaccination in Montanide Adjuvant Induces and GM-CSF Increases CXCR3 and Cutaneous Lymphocyte Antigen Expression by Tumor Antigen–Specific CD8 T Cells
Authors: Clancy-Thompson Eleanor , King Laura K. , Nunnley Lenora D. , Mullins Irene M. , Slingluff Craig L. , Mullins David W.
Published: April 2023

PDF file - 548K, Supplemental Figure 2: Representative staining for surface and intracellular CXCR3.
Supplementary Table 2 from Computational Immune Monitoring Reveals Abnormal Double-Negative T Cells Present across Human Tumor Types
Authors: Greenplate Allison R. , McClanahan Daniel D. , Oberholtzer Brian K. , Doxie Deon B. , Roe Caroline E. , Diggins Kirsten E. , Leelatian Nalin , Rasmussen Megan L. , Kelley Mark C. , Gama Vivian , Siska Peter J. , Rathmell Jeffrey C. , Ferrell P. Brent , Johnson Douglas B. , Irish Jonathan M.
Published: April 2023

Supplementary table containing the mass cytometry staining panels used in this manuscript.
Figure S8 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 S8 shows killing of CT26.hGUCY2C cells by 5F9.m28BBz CAR-T cells by β-galactosidase-release assay.
Figure S5 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 S5 shows detection of 5F9.m28BBz CAR surface expression by soluble GUCY2C binding.
Figure S4 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 S4 shows the human CAR construct sequence used in the paper.