bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from KIR3DL3 Is an Inhibitory Receptor for HHLA2 that Mediates an Alternative Immunoinhibitory Pathway to PD1
Authors: Bhatt Rupal S. , Berjis Abdulla , Konge Julie C. , Mahoney Kathleen M. , Klee Alyssa N. , Freeman Samuel S. , Chen Chun-Hau , Jegede Opeyemi A. , Catalano Paul J. , Pignon Jean-Christophe , Sticco-Ivins Maura , Zhu Baogong , Hua Ping , Soden Jo , Zhu Jie , McDermott David F. , Arulanandam Antonio R. , Signoretti Sabina , Freeman Gordon J.
Published: April 2023

Abstract
Blockade of the PD1 pathway is a broadly effective cancer therapy, but additional immune-inhibitory pathways contribute to tumor immune evasion. HERV–H LTR-associating 2 (HHLA2; also known as B7H5 and B7H7) is a member of the B7 family of immunoregulatory ligands that mediates costimulatory effects through its interaction with the CD28 family member transmembrane and immunoglobulin domain containing 2 (TMIGD2). However, HHLA2 has also been known to have inhibitory effects on T cells. Here, we report that we have identified killer cell immunoglobulin-like receptor, three immunoglobulin domains and long cytoplasmic tail 3 (KIR3DL3) as an inhibitory receptor for HHLA2 in T cells and natural killer (NK) cells and have generated HHLA2 and KIR3DL3 antibodies that block the immune-inhibitory activity of HHLA2, preserving the costimulatory signal. It is known that HHLA2 is frequently expressed in several tumor types, including clear cell renal cell carcinoma (ccRCC). We found that HHLA2 expression was nonoverlapping with PDL1 expression in ccRCC, suggesting that HHLA2 mediates a mechanism of tumor immune evasion that is independent from PDL1. Blockade of both the PD1 and KIR3DL3 pathways may be a more effective way to reverse tumor immune evasion.

See related Spotlight on p. 128
Data from TMB and Inflammatory Gene Expression Associated with Clinical Outcomes following Immunotherapy in Advanced Melanoma
Authors: Hodi F. Stephen , Wolchok Jedd D. , Schadendorf Dirk , Larkin James , Long Georgina V. , Qian Xiaozhong , Saci Abdel , Young Tina C. , Srinivasan Sujaya , Chang Han , Tang Hao , Wind-Rotolo Megan , Rizzo Jasmine I. , Jackson Donald G. , Ascierto Paolo A.
Published: April 2023

Abstract
Outcomes for patients with melanoma have improved over the past decade as a result of the development and FDA approval of immunotherapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand 1 (PD-L1). However, these therapies do not benefit all patients, and an area of intensive research investigation is identifying biomarkers that can predict which patients are most likely to benefit from them. Here, we report exploratory analyses of the associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival, and overall survival in patients with advanced melanoma treated as part of the CheckMate 066 and 067 phase III clinical trials evaluating immuno-oncology therapies. In patients enrolled in CheckMate 067 receiving the anti–PD-1 inhibitor nivolumab (NIVO) alone or in combination with the anti–CTLA-4 inhibitor ipilimumab (IPI) or IPI alone, longer survival appeared to associate with high (>median) versus low (≤median) TMB and with high versus low inflammatory signature scores. For NIVO-treated patients, the results regarding TMB association were confirmed in CheckMate 066. In addition, improved survival was observed with high TMB and absence of BRAF mutation. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immune checkpoint blockade in advanced melanoma.
Data from Tumor Cell–Derived TGFβ1 Attenuates Antitumor Immune Activity of T Cells via Regulation of PD-1 mRNA
Authors: Wu Pengfei , Geng Bo , Chen Qun , Zhao Enyang , Liu Jiang , Sun Chen , Zha Caijun , Shao Yong , You Bosen , Zhang Wenfu , Li Lulu , Meng Xiangqi , Cai Jinquan , Li Xuedong
Published: April 2023

Abstract
Dysfunction in T-cell antitumor activity contributes to the tumorigenesis, progression, and poor outcome of clear cell renal cell carcinoma (ccRCC), with this dysfunction resulting from high expression of programmed cell death-1 (PD-1) in T cells. However, the molecular mechanisms maintaining high PD-1 expression in T cells have not been fully investigated in ccRCC. Here, we describe a mechanism underlying the regulation of PD-1 at the mRNA level and demonstrated its impact on T-cell dysfunction. Transcriptomic analysis identified a correlation between TGFβ1 and PD-1 mRNA levels in ccRCC samples. The mechanism underlying the regulation of PD-1 mRNA was then investigated in vitro and in vivo using syngeneic tumor models. We also observed that TGFβ1 had prognostic significance in patients with ccRCC, and its expression was associated with PD-1 mRNA expression. CcRCC-derived TGFβ1 activated P38 and induced the phosphorylation of Ser10 on H3, which recruited p65 to increase SRSF3 and SRSF5 expression in T cells. As a result, the half-life of PD-1 mRNA in T cells was prolonged. SRSF3 coordinated with NXF1 to induce PD-1 mRNA extranuclear transport in T cells. We then demonstrated that TGFβ1 could induce SRSF3 expression to restrict the antitumor activity of T cells, which influenced immunotherapy outcomes in ccRCC mouse models. Our findings highlight that tumor-derived TGFβ1 mediates immune evasion and has potential as a prognostic biomarker and therapeutic target in ccRCC.

See related Spotlight on p. 1464
Data from A. Muciniphila Suppresses Colorectal Tumorigenesis by Inducing TLR2/NLRP3-Mediated M1-Like TAMs
Authors: Fan Lina , Xu Chaochao , Ge Qiwei , Lin Yifeng , Wong Chi Chun , Qi Yadong , Ye Bin , Lian Qingwu , Zhuo Wei , Si Jianmin , Chen Shujie , Wang Liangjing
Published: April 2023

Abstract
The interplay between gut microbiota and the host immune system is emerging as a factor in the pathogenesis of colorectal cancer. Here, we set out to identify the effect of Akkermansia muciniphila (A. muciniphila) on colorectal cancer pathogenesis. A. muciniphila abundance was significantly reduced in patients with colorectal cancer from two independent clinical cohorts and the GMrepo dataset. Supplementation with A. muciniphila suppressed colonic tumorigenesis in ApcMin/+ mice and the growth of implanted HCT116 or CT26 tumors in nude mice. Mechanistically, A. muciniphila facilitated enrichment of M1-like macrophages in an NLRP3-dependent manner in vivo and in vitro. As a consequence, NLRP3 deficiency in macrophages attenuated the tumor-suppressive effect of A. muciniphila. In addition, we revealed that TLR2 was essential for the activation of the NF-κB/NLRP3 pathway and A. muciniphila induced M1-like macrophage response. We observed positive correlations between M1-like macrophages, NLRP3/TLR2 and A. muciniphila in patients with colorectal cancer, which corroborated these findings. In summary, A. muciniphila–induced M1-like macrophages provide a therapeutic target in the colorectal cancer tumor microenvironment.
Data from Demographic Factors Associated with Toxicity in Patients Treated with Anti–Programmed Cell Death-1 Therapy
Authors: Shah Kaustav P. , Song Haocan , Ye Fei , Moslehi Javid J. , Balko Justin M. , Salem Joe-Elie , Johnson Douglas B.
Published: April 2023

Abstract
Immune checkpoint inhibitors (ICI) are now routinely used in multiple cancers but may induce autoimmune-like side effects known as immune-related adverse events (irAE). Although classical autoimmune diseases have well-known risk factors, including age, gender, and seasonality, the clinical factors that lead to irAEs are not well-defined. To explore these questions, we assessed 455 patients with advanced melanoma treated with ICI at our center and a large pharmacovigilance database (VigiBase). We found that younger age was associated with a similar rate of any irAEs but more frequent severe irAEs and more hospitalizations (OR, 0.97 per year). Paradoxically, however, older patients had more deaths and increased length of stay (LOS) when hospitalized. This was partially due to a distinct toxicity profile: Colitis and hepatitis were more common in younger patients, whereas myocarditis and pneumonitis had an older age distribution both in our center and in VigiBase. This pattern was particularly apparent with combination checkpoint blockade with ipilimumab and nivolumab. We did not find a link between gender or seasonality on development of irAEs in univariate or multivariate analyses, although winter hospitalizations were associated with marginally increased LOS. This study identifies age-specific associations of irAEs.
Data from Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment during Chemoradiotherapy Is Prognostic in HPV16+ Cancers
Authors: Colbert Lauren E. , El Molly B. , Lynn Erica J. , Bronk Julianna , Karpinets Tatiana V. , Wu Xiaogang , Chapman Bhavana V. , Sims Travis T. , Lin Daniel , Kouzy Ramez , Sammouri Julie , Biegert Greyson , Delgado Medrano Andrea Y. , Olvera Adilene , Sastry K. Jagannadha , Eifel Patricia J. , Jhingran Anuja , Lin Lilie , Ramondetta Lois M. , Futreal Andrew P. , Jazaeri Amir A. , Schmeler Kathleen M. , Yue Jingyan , Mitra Aparna , Yoshida-Court Kyoko , Wargo Jennifer A. , Solley Travis N. , Hegde Venkatesh , Nookala Sita S. , Yanamandra Ananta V. , Dorta-Estremera Stephanie , Mathew Geena , Kavukuntla Rohit , Papso Cassidy , Ahmed-Kaddar Mustapha , Kim Minsoo , Zhang Jianhua , Reuben Alexandre , Holliday Emma B. , Minsky Bruce D. , Koong Albert C. , Koay Eugene J. , Das Prajnan , Taniguchi Cullen M. , Klopp Ann
Published: April 2023

Abstract
Human papillomavirus (HPV) infection causes 600,000 new cancers worldwide each year. HPV-related cancers express the oncogenic proteins E6 and E7, which could serve as tumor-specific antigens. It is not known whether immunity to E6 and E7 evolves during chemoradiotherapy or affects survival. Using T cells from 2 HPV16+ patients, we conducted functional T-cell assays to identify candidate HPV-specific T cells and common T-cell receptor motifs, which we then analyzed across 86 patients with HPV-related cancers. The HPV-specific clones and E7-related T-cell receptor motifs expanded in the tumor microenvironment over the course of treatment, whereas non–HPV-specific T cells did not. In HPV16+ patients, improved recurrence-free survival was associated with HPV-responsive T-cell expansion during chemoradiotherapy.
Data from Molecular Signature of Tumor-Associated High Endothelial Venules That Can Predict Breast Cancer Survival
Authors: Sawada Junko , Hiraoka Nobuyoshi , Qi Rongsu , Jiang Lu , Fournier-Goss Ashley E. , Yoshida Masayuki , Kawashima Hiroto , Komatsu Masanobu
Published: April 2023

Abstract
High endothelial venules (HEV) are specialized post-capillary venules that recruit naïve lymphocytes to lymph nodes. HEVs are essential for the development of adaptive immunity. HEVs can also develop in tumors where they are thought to be important for recruiting naïve T cells and B cells into the tumors and locally enhancing antitumor immunity by supporting the formation of tertiary lymphoid structures. Herein, we used comparative transcriptome analysis of human breast cancer to investigate genes differentially expressed between tumor-associated HEVs and the rest of the tumor vasculature. Tumor vessels highly expressing HEV-upregulated genes, such as the homeobox gene MEOX2 and the tetraspanin gene TSPAN7, were associated with extensive infiltration of T and B cells and the occurrence of tertiary lymphoid structures, which is known to predict therapeutic responses to immune-checkpoint inhibitors. Moreover, high transcript counts of these genes in clinical tumor specimens were associated with a significant survival benefit in advanced breast cancer. The molecular signature of HEVs identified herein may be useful for guiding immunotherapies and provides a new direction for investigating tumor-associated HEVs and their clinical significance.

See related Spotlight by Gallimore, p. 371.
Data from NKG7 Is a T-cell–Intrinsic Therapeutic Target for Improving Antitumor Cytotoxicity and Cancer Immunotherapy
Authors: Wen Ti , Barham Whitney , Li Ying , Zhang Henan , Gicobi Joanina K. , Hirdler Jacob B. , Liu Xin , Ham Hyoungjun , Peterson Martinez Kodi E. , Lucien Fabrice , Lavoie Roxane R. , Li Hu , Correia Cristina , Monie Dileep D. , An Zesheng , Harrington Susan M. , Wu Xiaosheng , Guo Ruifeng , Dronca Roxana S. , Mansfield Aaron S. , Yan Yiyi , Markovic Svetomir N. , Park Sean S. , Sun Jie , Qin Hong , Liu Minetta C. , Vasmatzis George , Billadeau Daniel D. , Dong Haidong
Published: April 2023

Abstract
Cytotoxic CD8+ T cells (CTL) are a crucial component of the immune system notable for their ability to eliminate rapidly proliferating malignant cells. However, the T-cell intrinsic factors required for human CTLs to accomplish highly efficient antitumor cytotoxicity are not well defined. By evaluating human CD8+ T cells from responders versus nonresponders to treatment with immune checkpoint inhibitors, we sought to identify key factors associated with effective CTL function. Single-cell RNA-sequencing analysis of peripheral CD8+ T cells from patients treated with anti–PD-1 therapy showed that cells from nonresponders exhibited decreased expression of the cytolytic granule-associated molecule natural killer cell granule protein-7 (NKG7). Functional assays revealed that reduced NKG7 expression altered cytolytic granule number, trafficking, and calcium release, resulting in decreased CD8+ T-cell–mediated killing of tumor cells. Transfection of T cells with NKG7 mRNA was sufficient to improve the tumor-cell killing ability of human T cells isolated from nonresponders and increase their response to anti–PD-1 or anti–PD-L1 therapy in vitro. NKG7 mRNA therapy also improved the antitumor activity of murine tumor antigen–specific CD8+ T cells in an in vivo model of adoptive cell therapy. Finally, we showed that the transcription factor ETS1 played a role in regulating NKG7 expression. Together, our results identify NKG7 as a necessary component for the cytotoxic function of CD8+ T cells and establish NKG7 as a T-cell–intrinsic therapeutic target for enhancing cancer immunotherapy.

See related article by Li et al., p. 154.
Data from The SETDB1–TRIM28 Complex Suppresses Antitumor Immunity
Authors: Lin Jianhuang , Guo Dajiang , Liu Heng , Zhou Wei , Wang Chen , Müller Iris , Kossenkov Andrew V. , Drapkin Ronny , Bitler Benjamin G. , Helin Kristian , Zhang Rugang
Published: April 2023

Abstract
The tumor immune microenvironment is influenced by the epigenetic landscape of the tumor. Here, we have identified the SETDB1–TRIM28 complex as a critical suppressor of antitumor immunity. An epigenetic CRISPR–Cas9 screen of 1,218 chromatin regulators identified TRIM28 as a suppressor of PD-L1 expression. We then revealed that expression of the SETDB1–TRIM28 complex negatively correlated with infiltration of effector CD8+ T cells. Inhibition of SETDB1–TRIM28 simultaneously upregulated PD-L1 and activated the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) innate immune response pathway to increase infiltration of CD8+ T cells. Mechanistically, SETDB1–TRIM28 inhibition led to micronuclei formation in the cytoplasm, which is known to activate the cGAS–STING pathway. Thus, SETDB1–TRIM28 inhibition bridges innate and adaptive immunity. Indeed, SETDB1 knockout enhanced the antitumor effects of immune checkpoint blockade with anti–PD-L1 in a mouse model of ovarian cancer in a cGAS-dependent manner. Our findings establish the SETDB1–TRIM28 complex as a regulator of antitumor immunity and demonstrate that its loss activates cGAS–STING innate immunity to boost the antitumor effects of immune checkpoint blockade.
Data from A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors
Authors: Young David J. , Nguyen Bao , Li Li , Higashimoto Tomoyasu , Levis Mark J. , Liu Jun O. , Small Donald
Published: April 2023

Abstract
FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia and a target for tyrosine kinase inhibitors (TKI). FLT3 TKIs have yielded limited improvements to clinical outcomes. One reason for this is TKI inhibition by endogenous factors. We characterized plasma protein binding of FLT3 TKI, specifically staurosporine derivatives (STS-TKI) by alpha-1-acid glycoprotein (AGP), simulating its effects upon drug efficacy. Human AGP inhibits the antiproliferative activity of STS-TKI in FLT3/ITD-dependent cells, with IC50 shifts higher than clinically achievable. This is not seen with nonhuman plasma. Mifepristone cotreatment, with its higher AGP affinity, improves TKI activity despite AGP, yielding IC50s predicted to be clinically effective. In a mouse model of AGP drug inhibition, mifepristone restores midostaurin activity. This suggests combinatorial methods for overcoming plasma protein inhibition of existing TKIs for leukemia as well as providing a platform for investigating the drug–protein interaction space for developing more potent small-molecule agents.
Significance:
Our data provide a mechanism for the failure of some previous TKI clinical trials. The ability of mifepristone to disinhibit TKIs suggests an approach by which the combination of TKIs with already approved and well-tolerated drugs may restore TKI activity.

This article is highlighted in the In This Issue feature, p. 403
Data from Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators
Authors: Fornerod Maarten , Ma Jing , Noort Sanne , Liu Yu , Walsh Michael P. , Shi Lei , Nance Stephanie , Liu Yanling , Wang Yuanyuan , Song Guangchun , Lamprecht Tamara , Easton John , Mulder Heather L. , Yergeau Donald , Myers Jacquelyn , Kamens Jennifer L. , Obeng Esther A. , Pigazzi Martina , Jarosova Marie , Kelaidi Charikleia , Polychronopoulou Sophia , Lamba Jatinder K. , Baker Sharyn D. , Rubnitz Jeffrey E. , Reinhardt Dirk , van den Heuvel-Eibrink Marry M. , Locatelli Franco , Hasle Henrik , Klco Jeffery M. , Downing James R. , Zhang Jinghui , Pounds Stanley , Zwaan C. Michel , Gruber Tanja A.
Published: April 2023

Abstract
Genomic characterization of pediatric patients with acute myeloid leukemia (AML) has led to the discovery of somatic mutations with prognostic implications. Although gene-expression profiling can differentiate subsets of pediatric AML, its clinical utility in risk stratification remains limited. Here, we evaluate gene expression, pathogenic somatic mutations, and outcome in a cohort of 435 pediatric patients with a spectrum of pediatric myeloid-related acute leukemias for biological subtype discovery. This analysis revealed 63 patients with varying immunophenotypes that span a T-lineage and myeloid continuum designated as acute myeloid/T-lymphoblastic leukemia (AMTL). Within AMTL, two patient subgroups distinguished by FLT3-ITD and PRC2 mutations have different outcomes, demonstrating the impact of mutational composition on survival. Across the cohort, variability in outcomes of patients within isomutational subsets is influenced by transcriptional identity and the presence of a stem cell–like gene-expression signature. Integration of gene expression and somatic mutations leads to improved risk stratification.
Significance:
Immunophenotype and somatic mutations play a significant role in treatment approach and risk stratification of acute leukemia. We conducted an integrated genomic analysis of pediatric myeloid malignancies and found that a combination of genetic and transcriptional readouts was superior to immunophenotype and genomic mutations in identifying biological subtypes and predicting outcomes.

This article is highlighted in the In This Issue feature, p. 549
Data from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors
Authors: Shaffer Arthur L. , Phelan James D. , Wang James Q. , Huang DaWei , Wright George W. , Kasbekar Monica , Choi Jaewoo , Young Ryan M. , Webster Daniel E. , Yang Yandan , Zhao Hong , Yu Xin , Xu Weihong , Roulland Sandrine , Ceribelli Michele , Zhang Xiaohu , Wilson Kelli M. , Chen Lu , McKnight Crystal , Klumpp-Thomas Carleen , Thomas Craig J. , Häupl Björn , Oellerich Thomas , Rae Zachary , Kelly Michael C. , Ahn Inhye E. , Sun Clare , Gaglione Erika M. , Wilson Wyndham H. , Wiestner Adrian , Staudt Louis M.
Published: April 2023

Abstract
The use of Bruton tyrosine kinase (BTK) inhibitors to block B-cell receptor (BCR)–dependent NF-κB activation in lymphoid malignancies has been a major clinical advance, yet acquired therapeutic resistance is a recurring problem. We modeled the development of resistance to the BTK inhibitor ibrutinib in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma, which relies on chronic active BCR signaling for survival. The primary mode of resistance was epigenetic, driven in part by the transcription factor TCF4. The resultant phenotypic shift altered BCR signaling such that the GTPase RAC2 substituted for BTK in the activation of phospholipase Cγ2, thereby sustaining NF-κB activity. The interaction of RAC2 with phospholipase Cγ2 was also increased in chronic lymphocytic leukemia cells from patients with persistent or progressive disease on BTK inhibitor treatment. We identified clinically available drugs that can treat epigenetic ibrutinib resistance, suggesting combination therapeutic strategies.
Significance:
In diffuse large B-cell lymphoma, we show that primary resistance to BTK inhibitors is due to epigenetic rather than genetic changes that circumvent the BTK blockade. We also observed this resistance mechanism in chronic lymphocytic leukemia, suggesting that epigenetic alterations may contribute more to BTK inhibitor resistance than currently thought.

See related commentary by Pasqualucci, p. 555.

This article is highlighted in the In This Issue feature, p. 549
Table S1 from Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity
Authors: Steinkamp Mara P. , Lagutina Irina , Brayer Kathryn J. , Schultz Fred , Burke Danielle , Pankratz Vernon S. , Adams Sarah F. , Hudson Laurie G. , Ness Scott A. , Wandinger-Ness Angela
Published: April 2023

Antibodies used for flow cytometry and IHC analysis
Data from Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors
Authors: George Joshy , Chen Yaohui , Abdelfattah Nourhan , Yamamoto Keiko , Gallup Thomas D. , Adamson Scott I. , Rybinski Brad , Srivastava Anuj , Kumar Parveen , Lee Min Gyu , Baskin David S. , Jiang Wen , Choi Jong Min , Flavahan William , Chuang Jeffrey H. , Kim Betty Y.S. , Xu Jiaqiong , Jung Sung Yun , Yun Kyuson
Published: April 2023

The emergence of treatment resistance significantly reduces the clinical utility of many effective targeted therapies. Although both genetic and epigenetic mechanisms of drug resistance have been reported, whether these mechanisms are stochastically selected in individual tumors or governed by a predictable underlying principle is unknown. Here, we report that the dependence of cancer stem cells (CSC), not bulk tumor cells, on the targeted pathway determines the molecular mechanism of resistance in individual tumors. Using both spontaneous and transplantable mouse models of sonic hedgehog (SHH) medulloblastoma treated with a SHH/Smoothened inhibitor (SMOi), sonidegib/LDE225, we show that genetic-based resistance occurs only in tumors that contain SHH-dependent CSCs. In contrast, SHH medulloblastomas containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSC) acquire resistance through epigenetic reprogramming. Mechanistically, elevated proteasome activity in SMOi-resistant SI-CSC medulloblastomas alters the tumor cell maturation trajectory through enhanced degradation of specific epigenetic regulators, including histone acetylation machinery components, resulting in global reductions in H3K9Ac, H3K14Ac, H3K56Ac, H4K5Ac, and H4K8Ac marks and gene expression changes. These results provide new insights into how selective pressure on distinct tumor cell populations contributes to different mechanisms of resistance to targeted therapies. This insight provides a new conceptual framework to understand responses and resistance to SMOis and other targeted therapies.
Significance:
The mechanism by which individual tumors become resistant to targeted therapies is thought to be unpredictable. This study provides novel insights into how selective pressure on cancer stem versus bulk tumor cells drives distinct and predictable mechanisms of resistance to targeted therapies. This finding paves a way for future treatment strategies that incorporate anticipated resistance mechanisms in devising second-line therapies in a personalized manner.
Data from Na+/H+-exchanger 1 Enhances Antitumor Activity of Engineered NK-92 Natural Killer Cells
Authors: Gong Yao-Yu , Shao Hongguang , Li Yu , Brafford Patricia , Stine Zachary E. , Sun Jing , Felsher Dean W. , Orange Jordan S. , Albelda Steven M. , Dang Chi V.
Published: April 2023

Adoptive cell transfer (ACT) immunotherapy has remarkable efficacy against some hematologic malignancies. However, its efficacy in solid tumors is limited by the adverse tumor microenvironment (TME) conditions, most notably that acidity inhibits T and natural killer (NK) cell mTOR complex 1 (mTORC1) activity and impairs cytotoxicity. In several reported studies, systemic buffering of tumor acidity enhanced the efficacy of immune checkpoint inhibitors. Paradoxically, we found in a MYC–driven hepatocellular carcinoma model that systemic buffering increased tumor mTORC1 activity, negating inhibition of tumor growth by anti-PD1 treatment. Therefore, in this proof-of-concept study, we tested the metabolic engineering of immune effector cells to mitigate the inhibitory effect of tumor acidity while avoiding side effects associated with systemic buffering. We first overexpressed an activated RHEB in the human NK cell line NK-92, thereby rescuing acid-blunted mTORC1 activity and enhancing cytolytic activity. Then, to directly mitigate the effect of acidity, we ectopically expressed acid extruder proteins. Whereas ectopic expression of carbonic anhydrase IX (CA9) moderately increased mTORC1 activity, it did not enhance effector function. In contrast, overexpressing a constitutively active Na+/H+-exchanger 1 (NHE1; SLC9A1) in NK-92 did not elevate mTORC1 but enhanced degranulation, target engagement, in vitro cytotoxicity, and in vivo antitumor activity. Our findings suggest the feasibility of overcoming the inhibitory effect of the TME by metabolically engineering immune effector cells, which can enhance ACT for better efficacy against solid tumors.
Significance:
This study demonstrates the feasibility of metabolic engineering immune effector cells to overcome inhibition in the TME, an approach that could enhance the efficacy of adoptive transfer immunotherapy.
Data from Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity
Authors: Nepal Mahesh R. , Taheri Hanieh , Li Yang , Talebi Zahra , Uddin Muhammad Erfan , Jin Yan , DiGiacomo Duncan F. , Gibson Alice A. , Lustberg Maryam B. , Hu Shuiying , Sparreboom Alex
Published: April 2023

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a debilitating side effect that afflicts approximately 90% of patients that is initiated by OCT2-dependent uptake of oxaliplatin in dorsal root ganglion (DRG) neurons. The antidepressant drug duloxetine has been used to treat OIPN, although its usefulness in preventing this side effect remains unclear. We hypothesized that duloxetine has OCT2-inhibitory properties and can be used as an adjunct to oxaliplatin-based regimens to prevent OIPN. Transport studies were performed in cells stably transfected with mouse or human OCT2 and in isolated mouse DRG neurons ex vivo. Wild-type and OCT2-deficient mice were used to assess effects of duloxetine on hallmarks of OIPN, endogenous OCT2 biomarkers, and the pharmacokinetics of oxaliplatin, and the translational feasibility of a duloxetine-oxaliplatin combination was evaluated in various models of colorectal cancer. We found that duloxetine potently inhibited the OCT2-mediated transport of several xenobiotic substrates, including oxaliplatin, in a reversible, concentration-dependent manner, and independent of species and cell context. Furthermore, duloxetine restricted access of these substrates to DRG neurons ex vivo and prevented OIPN in wild-type mice to a degree similar to the complete protection observed in OCT2-deficient mice, without affecting the plasma levels of oxaliplatin. Importantly, the uptake and cytotoxicity of oxaliplatin in tumor cell lines in vitro and in vivo were not negatively influenced by duloxetine. The observed OCT2-targeting properties of duloxetine, combined with the potential for clinical translation, provide support for its further exploration as a therapeutic candidate for studies aimed at preventing OIPN in patients with cancer requiring treatment with oxaliplatin.
Significance:
We found that duloxetine has potent OCT2-inhibitory properties and can diminish excessive accumulation of oxaliplatin into DRG neurons. In addition, pretreatment of mice with duloxetine prevented OIPN without significantly altering the plasma pharmacokinetics and antitumor properties of oxaliplatin. These results suggest that intentional inhibition of OCT2-mediated transport by duloxetine can be employed as a prevention strategy to ameliorate OIPN without compromising the effectiveness of oxaliplatin-based treatment.
Data from Persistent Ethnicity-Associated Disparity in Antitumor Effectiveness of Immune Checkpoint Inhibitors Despite Equal Access
Authors: Florez Marcus A. , Kemnade Jan O. , Chen Nan , Du Wendy , Sabichi Anita L. , Wang Daniel Y. , Huang Quillan , Miller-Chism Courtney N. , Jotwani Aparna , Chen Albert C. , Hernandez David , Sandulache Vlad C.
Published: April 2023

We reviewed response to immune checkpoint inhibitors (ICI) of 207 patients with diagnoses of lung or head and neck cancer treated with chemotherapy/ICI combination therapy and ICI monotherapy between 2015 and 2020 at one of three clinical pavilions associated with the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine (Houston, TX). Two of these pavilions (Harris Health System and the Michael E. DeBakey Veterans Affairs Medical Center) serve large minority populations and provide equal access to care regardless of means. 174 patients had a diagnosis of lung cancer (non–small cell or small cell) and 33 had a diagnosis of head and neck squamous cell carcinoma (HNSCC). 38% self-identified as Black, 45% as non-Hispanic White, and 18% as Hispanic. The objective response rate (ORR) was similar for patients with lung cancer (35.057%) and HNSCC (30.3%; P = 0.894). The ORR for Hispanic and Black patients was lower compared with non-Hispanic White patients (H 27.0%, B 32.5%, W 38.7%; H vs. W P = 0.209; B vs. W P = 0.398). When considering only patients treated with ICI monotherapy, the ORR for Hispanic patients dropped further to 20.7% while the ORR of Black and non-Hispanic White patients remained about the same (B 29.3% and W 35.9%, H vs. W P = 0.133; B vs. W P = 0.419). Immune-related adverse events were the lowest in the Hispanic population occurring in only 30% of patients compared with 40% of patients in the Black cohort and 50% of the non-Hispanic White cohorts.
Significance:
To our knowledge, this report is the first to compare ICI effectiveness within a diverse patient population with a substantial Black and Hispanic NSCLC and HNSCC patient population treated in the context of equal access to care. The data presented in this article suggests reduced effectiveness of ICI monotherapy in Hispanic patients and thereby underscores the need for improved access and representation of racial/ethnic minority patients in ICI clinical trials.
Data from Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity
Authors: Steinkamp Mara P. , Lagutina Irina , Brayer Kathryn J. , Schultz Fred , Burke Danielle , Pankratz Vernon S. , Adams Sarah F. , Hudson Laurie G. , Ness Scott A. , Wandinger-Ness Angela
Published: April 2023

Abstract
The importance of the immune microenvironment in ovarian cancer progression, metastasis, and response to therapies has become increasingly clear, especially with the new emphasis on immunotherapies. To leverage the power of patient-derived xenograft (PDX) models within a humanized immune microenvironment, three ovarian cancer PDXs were grown in humanized NBSGW (huNBSGW) mice engrafted with human CD34+ cord blood–derived hematopoietic stem cells. Analysis of cytokine levels in the ascites fluid and identification of infiltrating immune cells in the tumors demonstrated that these humanized PDX (huPDX) established an immune tumor microenvironment similar to what has been reported for patients with ovarian cancer. The lack of human myeloid cell differentiation has been a major setback for humanized mouse models, but our analysis shows that PDX engraftment increases the human myeloid population in the peripheral blood. Analysis of cytokines within the ascites fluid of huPDX revealed high levels of human M-CSF, a key myeloid differentiation factor as well as other elevated cytokines that have previously been identified in ovarian cancer patient ascites fluid including those involved in immune cell differentiation and recruitment. Human tumor-associated macrophages and tumor-infiltrating lymphocytes were detected within the tumors of humanized mice, demonstrating immune cell recruitment to tumors. Comparison of the three huPDX revealed certain differences in cytokine signatures and in the extent of immune cell recruitment. Our studies show that huNBSGW PDX models reconstitute important aspects of the ovarian cancer immune tumor microenvironment, which may recommend these models for preclinical therapeutic trials.
Significance:
huPDX models are ideal preclinical models for testing novel therapies. They reflect the genetic heterogeneity of the patient population, enhance human myeloid differentiation, and recruit immune cells to the tumor microenvironment.
Data from Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity
Authors: Steinkamp Mara P. , Lagutina Irina , Brayer Kathryn J. , Schultz Fred , Burke Danielle , Pankratz Vernon S. , Adams Sarah F. , Hudson Laurie G. , Ness Scott A. , Wandinger-Ness Angela
Published: April 2023

The importance of the immune microenvironment in ovarian cancer progression, metastasis, and response to therapies has become increasingly clear, especially with the new emphasis on immunotherapies. To leverage the power of patient-derived xenograft (PDX) models within a humanized immune microenvironment, three ovarian cancer PDXs were grown in humanized NBSGW (huNBSGW) mice engrafted with human CD34+ cord blood–derived hematopoietic stem cells. Analysis of cytokine levels in the ascites fluid and identification of infiltrating immune cells in the tumors demonstrated that these humanized PDX (huPDX) established an immune tumor microenvironment similar to what has been reported for patients with ovarian cancer. The lack of human myeloid cell differentiation has been a major setback for humanized mouse models, but our analysis shows that PDX engraftment increases the human myeloid population in the peripheral blood. Analysis of cytokines within the ascites fluid of huPDX revealed high levels of human M-CSF, a key myeloid differentiation factor as well as other elevated cytokines that have previously been identified in ovarian cancer patient ascites fluid including those involved in immune cell differentiation and recruitment. Human tumor-associated macrophages and tumor-infiltrating lymphocytes were detected within the tumors of humanized mice, demonstrating immune cell recruitment to tumors. Comparison of the three huPDX revealed certain differences in cytokine signatures and in the extent of immune cell recruitment. Our studies show that huNBSGW PDX models reconstitute important aspects of the ovarian cancer immune tumor microenvironment, which may recommend these models for preclinical therapeutic trials.
Significance:
huPDX models are ideal preclinical models for testing novel therapies. They reflect the genetic heterogeneity of the patient population, enhance human myeloid differentiation, and recruit immune cells to the tumor microenvironment.
Mitochondrial Metabolism Drives Low-density Lipoprotein-induced Breast Cancer Cell Migration
Authors: Nóbrega-Pereira Sandrina , Santos Francisco , Oliveira Santos Miguel , Serafim Teresa L. , Lopes Ana Patrícia , Coutinho Diogo , Carvalho Filipa S. , Domingues Rosário M. , Domingues Pedro , Bernardes de Jesus Bruno , Morais Vanessa A. , Dias Sérgio
Published: April 2023

Most cancer-related deaths are due to metastases. Systemic factors, such as lipid-enriched environments [as low-density lipoprotein (LDL)-cholesterol], favor breast cancer, including triple-negative breast cancer (TNBC) metastasis formation. Mitochondria metabolism impacts TNBC invasive behavior but its involvement in a lipid-enriched setting is undisclosed. Here we show that LDL increases lipid droplets, induces CD36 and augments TNBC cells migration and invasion in vivo and in vitro. LDL induces higher mitochondrial mass and network spread in migrating cells, in an actin remodeling-dependent manner, and transcriptomic and energetic analyses revealed that LDL renders TNBC cells dependent on fatty acids (FA) usage for mitochondrial respiration. Indeed, engagement on FA transport into the mitochondria is required for LDL-induced migration and mitochondrial remodeling. Mechanistically, LDL treatment leads to mitochondrial long-chain fatty acid accumulation and increased reactive oxygen species (ROS) production. Importantly, CD36 or ROS blockade abolished LDL-induced cell migration and mitochondria metabolic adaptations. Our data suggest that LDL induces TNBC cells migration by reprogramming mitochondrial metabolism, revealing a new vulnerability in metastatic breast cancer.

Significance:

LDL induces breast cancer cell migration that relies on CD36 for mitochondrial metabolism and network remodeling, providing an antimetastatic metabolic strategy.
Utilization Of Modified SERVQUAL Model in Crafting Strategies Among Courier Services
Authors: Mendoza Xavier Lawrence D. , Pichay Sherina B. , Tadeo Jerico B.
Published: April 2023

Pandemic has a big impact on the whole economy especially on the business industry, most of the businesses are forcibly closed down due to the pandemic, and due to the safety measurements of the government, and businesses such as courier services are playing a vital role in building the gap between the customers and businesses. Hence, the study aimed to determine the customers’ evaluation on service quality of courier services in Tanza, Cavite. The researchers used a descriptive-correlational research design in this study. The result of the study depicted that majority of the courier service customer were female with 78.89% and age ranging from 21 to 30 years old. The majority of the participants were single. Also, College undergraduates obtained the highest percentage with 58.90%, as well as the net monthly income of the participants ranging less than Php 10,957.00. However, in terms of the customers’ level of satisfaction on the five dimensions of service quality, credibility got the highest grand mean which indicates that it is the factor that highly influences customer satisfaction. The overall satisfaction level of the participants showed that they were satisfied with the services of courier service providers. The researchers concluded that majority of courier service customers are female’s ages ranging from 21 to 30 years old. The researchers revealed that most of the courier service customers are college undergraduates and earning less than Php 10,957.00 per month. The researchers recommended strategies to courier services to improve their service quality.
Study Habit and Social Media Exposure as Predictors of Grade 10 Students Academic Performance
Authors: Castillas Glenn M.
Published: April 2023

The purpose of this study was to determine the respondents' study habits and social media exposure during the school year. 2019-2020.The study's participants were 50 grade 10 students of Alabel 4 District. The researcher administered the survey to all of the student respondents. Majority of respondents were 17 years old, and the majority of their parents had a bachelor's degree and were all employed.

The researcher administered the survey to all of the student respondents. The majority of respondents were 17 years old, and the majority of their parents had a bachelor's degree and were all employed. It also has a high correlation with respondents' social media exposure. The responses revealed that respondents' use of social media has a direct or indirect positive effect on their academic performance.

The study suggests that parents should constantly guide and supervise their children's use of social media, particularly female and younger students who are more interested in social networking. Despite the fact that this study discovered that respondents' socio-demographic characteristics have no bearing on their academic performance. It also suggests that a long-term program be implemented to assist students in constantly improving their study habits.

According to the study's findings, teachers must continue to effectively stimulate and sustain students' interests and enthusiasm for learning in order for them to consistently achieve exceptional academic performance. Teachers should receive regular service trainings and workshops to stay current on their knowledge and pedagogical skills, improve the quality of the teacher workforce, and improve students' academic achievement.
Circ‐myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia‐Inducible Factor‐1α Expression
Authors: Xing Yan , Qi Jing , Cheng Xiaohan , Song Xinyue , Zhang Jingya , Li Songyue , Zhao Xiaoting , Gong Ting , Yang Jiaxin , Zhao Chong , Xin Wei , Zhu Daling , Zheng Xiaodong
Published: April 2023

Background

Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of pulmonary hypertension (PH). Hypoxia‐inducible factor (HIF) is a well‐known modulator of hypoxia‐induced PH. The role and underlying mechanism of circRNAs in the regulation of HIF expression remains elusive.

Methods and Results

We profiled pulmonary artery transcriptomes using RNA sequencing and screened circRNAs associated with hypoxia treatment. The expression of a novel circRNA, circ_chr11_67292179–67294612 (circ‐myh8), was increased by hypoxia in a time‐dependent manner. We evaluated the effects of circ‐myh8 overexpression by adeno‐associated virus or inhibition by short hairpin RNA on proliferation and cell cycling in mice and pulmonary artery smooth muscle cells. Overexpression of circ‐myh8 promotes PH under normoxia, and disruption of circ‐myh8 by short hairpin RNA mitigates PH in chronic hypoxic mice. Biologically, circ‐myh8 induces the proliferation and cell‐cycle progression of pulmonary artery smooth muscle cells in vivo and in vitro. Mechanistically, RNA pull‐down and RNA immunoprecipitation assays were used to examine the interaction of circRNAs with the binding protein KAT7 (lysine acetyltransferase 7). The acetylation level of lysine 5 of histone H4 in the transcriptional initiation region of HIF1α was determined by chromatin immunoprecipitation assay followed by reverse transcription‐quantitative polymerase chain reaction. Circ‐myh8 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of HIF1α, which elicits acetylation of lysine 5 of histone H4 in their promoters.

Conclusions

Our findings not only reveal the pivotal roles of circ‐myh8 in governing histone modification in anti‐PH treatment but also advocate triggering the circ‐myh8/KAT7/HIF1α pathway to combat PH.
Towards Locally Embedded Beach Management Units in Tanzania for Legitimacy and Sustainability
Authors: Namkesa Faraja , Kweka Opportuna L.
Published: April 2023

Local embeddedness for beach management units is vital for legitimacy and sustainability. This paper employs the theory of local embeddedness to study the extent to which Beach Management Units (BMUs) will bring about the sustainability of fisheries at the community level. It draws from the perceptions of the communities living in Mtwara rural on how Beach Management Units are governed. Using key informant interviews in four villages of Mtwara rural, different levels of embeddedness were identified and measured. The findings show that although Beach Management Units were introduced to empower local communities to manage fisheries resources, they are not embedded within the community.
Bulbophyllum wiratnoi (Orchidaceae), a new species of section Epicrianthes from Indonesian New Guinea
Authors: SAPUTRA REZA , MUSTAQIM WENDY A. , CHAMPION JEFFREY , SCHUITEMAN ANDRE
Published: April 2023

A new species of Bulbophyllum sect. Epicrianthes, Bulbophyllum wiratnoi Saputra, Schuit., Mustaqim & J.Champ., is described based on specimens from Indonesian New Guinea. A detailed morphological description and diagnosis, information on distribution and ecology, a preliminary conservation assessment, and a discussion are provided. A key to species of Bulbophyllum sect. Epicrianthes in Indonesian New Guinea is also presented.
Phaeoisaria ellipsoidea (Pleurotheciaceae, Pleurotheciales, Sordariomycetes), a new lignicolous freshwater fungus from Xishuangbanna, Yunnan Province, China
Authors: YANG JUN-XIAN , ZHANG HUANG , WANG LIN , ZHU RONG , DONG WEI , CHEN SHOU-YUE
Published: April 2023

In this study, two lignicolous freshwater fungi were collected and isolated from submerged decaying wood in Manfeilong reservoir in Xishuangbanna, Yunnan Province, China. Based on the morphological characters and phylogenetic analyses of combined LSU, SSU, ITS and rpb2 sequence dataset, one is identified as a new species in Phaeoisaria, namely P. ellipsoidea, and the other is identified as Sterigmatobotrys rudis. Descriptions and illustrations of the two species are provided.
Aspidistra phongdiensis (Asparagaceae), a new species from Central Vietnam
Authors: CHINH VU TIEN , DINH DIEN , LE TUAN ANH , DOAN QUOC TUAN , LE NGOC TUAN , LE VAN HUONG , TRAN NAM THANG , VISLOBOKOV NIKOLAY A.
Published: April 2023

Aspidistra phongdiensis is described based on the specimen collected from the Thua Thien Hue province of Vietnam. The new species is morphologically similar to A. khangii but differs in wider leaf blade (vs. narrowly elliptic), perigone white outside (vs. purple mottled), yellow pollen (vs. white), introrse anthers (vs. latrorse) and widely obconic pistil (vs. desk-shaped).
Nomenclatural Notes on the name Euphorbia neorugosa (Euphobiaceae)
Authors: DENG YUN-FEI
Published: April 2023

N/A
Calceolaria nivalis subsp. lanatifolia, a new subspecies of Calceolariaceae from Northern Peru
Authors: PUPPO PAMELA
Published: April 2023

A new subspecies of Calceolaria nivalis, C. nivalis subsp. lanatifolia is described and illustrated. The new subspecies was collected in Uchumarca district, department of La Libertad, Peru, between 2300–3850 m elevation. Calceolaria nivalis subsp. lanatifolia is characterized by the lanate indumentum in the lower surface of the leaves, villous petioles, peduncles, and pedicels, and sepals with a strigose margin internally.