Medical Sciences Commons^™

Stmut: A Framework For Visualizing Somatic Alterations In Spatial Transcriptomics Data Of Cancer, Limin Chen, Darwin Chang, Bishal Tandukar, Delahny Deivendran, Joanna Pozniak, Noel Cruz-Pacheco, Raymond J Cho, Jeffrey Cheng, Iwei Yeh, Chris Marine, Boris C Bastian, Andrew L Ji, A Hunter Shain

Staff and Researcher Publications

Spatial transcriptomic technologies, such as the Visium platform, measure gene expression in different regions of tissues. Here, we describe new software, STmut, to visualize somatic point mutations, allelic imbalance, and copy number alterations in Visium data. STmut is tested on fresh-frozen Visium data, formalin-fixed paraffin-embedded (FFPE) Visium data, and tumors with and without matching DNA sequencing data. Copy number is inferred on all conditions, but the chemistry of the FFPE platform does not permit analyses of single nucleotide variants. Taken together, we propose solutions to add the genetic dimension to spatial transcriptomic data and describe the limitations of different datatypes.

Widespread Brca1/2-Independent Homologous Recombination Defects Are Caused By Alterations In Rna-Binding Proteins, Daniel J Mcgrail, Yang Li, Roger S Smith, Bin Feng, Hui Dai, Limei Hu, Briana Dennehey, Sharad Awasthi, Marc L Mendillo, Anil K Sood, Gordon B Mills, Shiaw-Yih Lin, S Stephen Yi, Nidhi Sahni

Faculty, Staff and Student Publications

Defects in homologous recombination DNA repair (HRD) both predispose to cancer development and produce therapeutic vulnerabilities, making it critical to define the spectrum of genetic events that cause HRD. However, we found that mutations in BRCA1/2 and other canonical HR genes only identified 10%-20% of tumors that display genomic evidence of HRD. Using a networks-based approach, we discovered that over half of putative genes causing HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA-binding protein (RBP)-encoding genes. These putative drivers of HRD were experimentally validated, cross-validated in an independent cohort, and enriched in cancer-associated …

Galectin-3 Cooperates With Cd47 To Suppress Phagocytosis And T-Cell Immunity In Gastric Cancer Peritoneal Metastases, Yibo Fan, Shumei Song, Yuan Li, Shilpa S Dhar, Jiankang Jin, Katsuhiro Yoshimura, Xiaodan Yao, Ruiping Wang, Ailing W Scott, Melissa Pool Pizzi, Jingjing Wu, Lang Ma, George A Calin, Samir Hanash, Linghua Wang, Michael Curran, Jaffer A Ajani

Faculty, Staff and Student Publications

UNLABELLED: The peritoneal cavity is a common site of gastric adenocarcinoma (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to current therapies and confers poor prognosis, highlighting the need to identify new therapeutic targets. CD47 conveys a "don't eat me" signal to myeloid cells upon binding its receptor signal regulatory protein alpha (SIRPα), which helps tumor cells circumvent macrophage phagocytosis and evade innate immune responses. Previous studies demonstrated that the blockade of CD47 alone results in limited clinical benefits, suggesting that other target(s) might need to be inhibited simultaneously with CD47 to elicit a strong antitumor response. Here, we found that …

The Cancer Moonshot Immuno-Oncology Translational Network At 5: Accelerating Cancer Immunotherapies, Ananth Annapragada, Andrew G Sikora, Himangi Marathe, Song Liu, Michael Demetriou, Lawrence Fong, Jinming Gao, Donald Kufe, Zachary S Morris, Eduardo Vilar, Elad Sharon, Alan Hutson, Kunle Odunsi

Faculty, Staff and Student Publications

The Immuno-Oncology Translational Network (IOTN) was established in 2018 as part of the Cancer Moonshot. In 2022, President Joe Biden set new goals to reduce the cancer death rate by half within 25 years and improve the lives of people with cancer and cancer survivors. The IOTN is focused on accelerating translation of cancer immunology research, from bench to bedside, and improving immunotherapy outcomes across a wide array of cancers in the adult population. The unique structure and team science approach of the IOTN is designed to accelerate discovery and evaluation of novel immune-based therapeutic and prevention strategies. In this …

Molecular Mechanisms Of Twist1-Regulated Transcription In Emt And Cancer Metastasis, Xiaobin Yu, Tao He, Zhangwei Tong, Lan Liao, Shixia Huang, Walid D Fakhouri, Dean P Edwards, Jianming Xu

Faculty, Staff and Students Publications

TWIST1 induces epithelial-to-mesenchymal transition (EMT) to drive cancer metastasis. It is yet unclear what determines TWIST1 functions to activate or repress transcription. We found that the TWIST1 N-terminus antagonizes TWIST1-regulated gene expression, cancer growth and metastasis. TWIST1 interacts with both the NuRD complex and the NuA4/TIP60 complex (TIP60-Com) via its N-terminus. Non-acetylated TWIST1-K73/76 selectively interacts with and recruits NuRD to repress epithelial target gene transcription. Diacetylated TWIST1-acK73/76 binds BRD8, a component of TIP60-Com that also binds histone H4-acK5/8, to recruit TIP60-Com to activate mesenchymal target genes and MYC. Knockdown of BRD8 abolishes TWIST1 and TIP60-Com interaction and TIP60-Com recruitment to …

The Deubiquitinase Zranb1 Is An E3 Ubiquitin Ligase For Slc7a11 And Regulates Ferroptotic Resistance, Shan Huang, Qimin Zhang, Manyu Zhao, Xing Wang, Yilei Zhang, Boyi Gan, Peijing Zhang

Faculty, Staff and Student Publications

The dependency of cancer cells on iron increases their susceptibility to ferroptosis, thus providing new opportunities for patients with treatment-resistant tumors. However, we show that lipid peroxidation, a hallmark of ferroptosis, was found in various areas of patient samples, indicating the potential resistance of ferroptosis. Using whole deubiquitinases (DUBs) sgRNA screening, we found that loss of ZRANB1 confers cancer cell resistance to ferroptosis. Intriguingly, functional studies revealed that ZRANB1 ubiquitinates and represses SLC7A11 expression as an E3 ubiquitin ligase and that ZRANB1 inhibits glutathione (GSH) synthesis through SLC7A11 degradation, leading to elevated lipid peroxidation and ferroptosis. Deletion of the region …

Rare De Novo Gain-Of-Function Missense Variants In Dot1l Are Associated With Developmental Delay And Congenital Anomalies, Zelha Nil, Ashish R Deshwar, Yan Huang, Scott Barish, Xi Zhang, Sanaa Choufani, Polona Le Quesne Stabej, Ian Hayes, Patrick Yap, Chad Haldeman-Englert, Carolyn Wilson, Trine Prescott, Kristian Tveten, Arve Vøllo, Devon Haynes, Patricia G Wheeler, Jessica Zon, Cheryl Cytrynbaum, Rebekah Jobling, Moira Blyth, Siddharth Banka, Alexandra Afenjar, Cyril Mignot, Florence Robin-Renaldo, Boris Keren, Oguz Kanca, Xiao Mao, Daniel J Wegner, Kathleen Sisco, Marwan Shinawi, Undiagnosed Disease Network, Michael F Wangler, Rosanna Weksberg, Shinya Yamamoto, Gregory Costain, Hugo J Bellen

Faculty, Staff and Students Publications

Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher. All probands had some degree of global developmental delay/intellectual disability, and most had one or more major congenital anomalies. To assess the pathogenicity of the DOT1L …

Identification And Initial Validation Of Maximal Tumor Area As A Novel Prognostic Factor For Overall And Disease-Free Survival In Patients With Resectable Colon Cancer: A Retrospective Study, Fei-Long Ning, Wan-Jie Gu, Lin-Zheng Dai, Wan-Ying Du, Yong-Ji Zeng, Jia-Kui Zhang, Masanobu Abe, Yan-Long Liu, Rui Zhang, Chun-Dong Zhang

Faculty, Staff and Students Publications

BACKGROUND: The tumor area may be a potential prognostic indicator. The present study aimed to determine and validate the prognostic value of tumor area in curable colon cancer.

METHODS: This retrospective study included a training and validation cohorts of patients who underwent radical surgery for colon cancer. Independent prognostic factors for overall survival (OS) and disease-free survival (DFS) were identified using Cox proportional hazards regression models. The prognostic discrimination was evaluated using the integrated area under the receiver operating characteristic curves (iAUCs) for prognostic factors and models. The prognostic discrimination between tumor area and other individual factors was compared, along …

Deep Learning-Based Dose Prediction To Improve The Plan Quality Of Volumetric Modulated Arc Therapy For Gynecologic Cancers, Mary P Gronberg, Anuja Jhingran, Tucker J Netherton, Skylar S Gay, Carlos E Cardenas, Christine Chung, David Fuentes, Clifton D Fuller, Rebecca M Howell, Meena Khan, Tze Yee Lim, Barbara Marquez, Adenike M Olanrewaju, Christine B Peterson, Ivan Vazquez, Thomas J Whitaker, Zachary Wooten, Ming Yang, Laurence E Court

Faculty, Staff and Student Publications

Background: In recent years, deep‐learning models have been used to predict entire three‐dimensional dose distributions. However, the usability of dose predictions to improve plan quality should be further investigated.

Purpose: To develop a deep‐learning model to predict high‐quality dose distributions for volumetric modulated arc therapy (VMAT) plans for patients with gynecologic cancer and to evaluate their usability in driving plan quality improvements.

Methods: A total of 79 VMAT plans for the female pelvis were used to train (47 plans), validate (16 plans), and test (16 plans) 3D dense dilated U‐Net models to predict 3D dose distributions. The models received the …

Operational Ontology For Oncology (O3): A Professional Society-Based, Multistakeholder, Consensus-Driven Informatics Standard Supporting Clinical And Research Use Of Real-World Data From Patients Treated For Cancer, Charles S Mayo, Mary U Feng, Kristy K Brock, Randi Kudner, Peter Balter, Jeffrey C Buchsbaum, Amanda Caissie, Elizabeth Covington, Emily C Daugherty, Andre L Dekker, Clifton D Fuller, Anneka L Hallstrom, David S Hong, Julian C Hong, Sophia C Kamran, Eva Katsoulakis, John Kildea, Andra V Krauze, Jon J Kruse, Tod Mcnutt, Michelle Mierzwa, Amy Moreno, Jatinder R Palta, Richard Popple, Thomas G Purdie, Susan Richardson, Gregory C Sharp, Shiraishi Satomi, Lawrence R Tarbox, Aradhana M Venkatesan, Alon Witztum, Kelly E Woods, Yuan Yao, Keyvan Farahani, Sanjay Aneja, Peter E Gabriel, Lubomire Hadjiiski, Dan Ruan, Jeffrey H Siewerdsen, Steven Bratt, Michelle Casagni, Su Chen, John C Christodouleas, Anthony Didonato, James Hayman, Rishhab Kapoor, Saul Kravitz, Sharon Sebastian, Martin Von Siebenthal, Walter Bosch, Coen Hurkmans, Sue S Yom, Ying Xiao

Faculty, Staff and Student Publications

PURPOSE: The ongoing lack of data standardization severely undermines the potential for automated learning from the vast amount of information routinely archived in electronic health records (EHRs), radiation oncology information systems, treatment planning systems, and other cancer care and outcomes databases. We sought to create a standardized ontology for clinical data, social determinants of health, and other radiation oncology concepts and interrelationships.

METHODS AND MATERIALS: The American Association of Physicists in Medicine's Big Data Science Committee was initiated in July 2019 to explore common ground from the stakeholders' collective experience of issues that typically compromise the formation of large inter- …

Adavosertib Enhances Antitumor Activity Of Trastuzumab Deruxtecan In Her2-Expressing Cancers, Timothy P Diperi, Kurt W Evans, Maria Gabriela Raso, Ming Zhao, Yasmeen Q Rizvi, Xiaofeng Zheng, Bailiang Wang, Bryce P Kirby, Kathleen Kong, Michael Kahle, Timothy A Yap, Ecaterina E Dumbrava, Jaffer A Ajani, Siqing Fu, Khandan Keyomarsi, Funda Meric-Bernstam

Faculty, Staff and Student Publications

PURPOSE: Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy.

EXPERIMENTAL DESIGN: Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to …

Next-Generation Chimeric Antigen Receptors For T- And Natural Killer-Cell Therapies Against Cancer, Ye Li, Katayoun Rezvani, Hind Rafei

Faculty, Staff and Student Publications

Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor-specific antigens that can be targeted without cross-reactivity against normal tissues. This may lead to unwanted on-target off-tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, …

Model-Informed Drug Development Of Autologous Car-T Cell Therapy: Strategies To Optimize Car-T Cell Exposure Leveraging Cell Kinetic/Dynamic Modeling, Anna M Mc Laughlin, Peter A Milligan, Cassian Yee, Martin Bergstrand

Faculty, Staff and Student Publications

Autologous Chimeric antigen receptor (CAR-T) cell therapy has been highly successful in the treatment of aggressive hematological malignancies and is also being evaluated for the treatment of solid tumors as well as other therapeutic areas. A challenge, however, is that up to 60% of patients do not sustain a long-term response. Low CAR-T cell exposure has been suggested as an underlying factor for a poor prognosis. CAR-T cell therapy is a novel therapeutic modality with unique kinetic and dynamic properties. Importantly, "clear" dose-exposure relationships do not seem to exist for any of the currently approved CAR-T cell products. In other …

Prevalence And Implications Of Significance Testing For Baseline Covariate Imbalance In Randomised Cancer Clinical Trials: The Table 1 Fallacy, Alexander D Sherry, Pavlos Msaouel, Zachary R Mccaw, Joseph Abi Jaoude, Eric J Hsu, Ramez Kouzy, Roshal Patel, Yumeng Yang, Timothy A Lin, Cullen M Taniguchi, Claus Rödel, Emmanouil Fokas, Chad Tang, Clifton David Fuller, Bruce Minsky, Tomer Meirson, Ryan Sun, Ethan B Ludmir

Faculty, Staff and Student Publications

Background: The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials.

Methods: From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy.

Results: A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating …

Political Ideology And Trust In Government Health Agencies For Cancer Information, Onyema G Chido-Amajuoyi, Henry K Onyeaka, Itunu O Sokale, Somto Nwani, Carlos H Barcenas, Hermioni L Amonoo, Sanjay Shete

Faculty, Staff and Students Publications

This cross-sectional study assesses the association between political ideology and trust in government health agencies for cancer information.

Loss Of Adar1 In Macrophages In Combination With Interferon Gamma Suppresses Tumor Growth By Remodeling The Tumor Microenvironment, Weiwei Lin, Yikai Luo, Jie Wu, Haowan Zhang, Ge Jin, Chahua Guo, Hang Zhou, Han Liang, Xiaoyan Xu

Faculty, Staff and Student Publications

Background: ADAR1, the major enzyme for RNA editing, has emerged as a tumor-intrinsic key determinant for cancer immunotherapy efficacy through modulating interferon-mediated innate immunity. However, the role of ADAR1 in innate immune cells such as macrophages remains unknown.

Methods: We first analyzed publicly accessible patient-derived single-cell RNA-sequencing and perturbed RNA sequencing data to elucidate the ADAR1 expression and function in macrophages. Subsequently, we evaluated the combined effects of ADAR1 conditional knockout in macrophages and interferon (IFN)-γ treatment on tumor growth in three distinct disease mouse models: LLC for lung cancer, B16-F10 for melanoma, and MC38 for colon cancer. To gain …

Supportive Care For Dual Caregivers Who Care For Their Partner With Cancer And Their Young Children, Sujin Ann-Yi, Kathrin Milbury, Morgan Jones, Victoria Necroto, Meagan Whisenant, Yisheng Li, Eduardo Bruera

Faculty, Staff and Student Publications

Purpose: Advanced cancer patients and their spouses who parent minor children report parenting concerns and increased psychological distress. This single-arm trial examined the feasibility and initial evidence for efficacy of a novel parent support program.

Methods: Patients with a metastatic solid malignancy and their spouses completed self-reported assessments of psychological distress (HADS), parenting concerns (PCQ) and efficacy (CaPSE) at baseline. Both patients and spouses jointly attended the first two sessions addressing illness communication and family routines. Spouses individually attended two additional sessions focusing on caregiver support and death preparedness. All four sessions were delivered via videoconference by a licensed psychological …

The Influence Of Obesity On Outcomes With Immune Checkpoint Blockade: Clinical Evidence And Potential Biological Mechanisms, Andrew W Hahn, Neha Venkatesh, Pavlos Msaouel, Jennifer L Mcquade

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) is a mainstay of treatment for advanced cancer, yet tumor response and host toxicity are heterogenous in those patients who receive ICB. There is growing interest in understanding how host factors interact with tumor intrinsic properties and the tumor microenvironment to influence the therapeutic index with ICB. Obesity, defined by body mass index, is a host factor associated with improved outcomes in select cancers when treated with ICB. While the biological mechanism for this obesity paradox is not fully understood, pre-clinical and translational studies suggest obesity may potentially impact tumor metabolism, inflammation, and angiogenesis. Herein, we …

Identification Of Dual Strn-Ntrk2 Rearrangements In A High Grade Sarcoma, With Good Clinical Response To First-Line Larotrectinib Therapy, Ruihe Lin, Atrayee Basu Mallick, Zi-Xuan Wang, Phd, Scot Andrew Brown, Bo Lu, Md, Wei Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Among the three NTRK genes, NTRK2 possesses a tremendous structural complexity and involves tumorigenesis of several types of tumors. To date, only STRN and RBPMS are identified in the fusion with NTRK2 in adult soft tissue tumors. More recently, the highly selective Trk tyrosine kinases inhibitors, including larotrectinib and entrectinib, have shown significant efficacy for treating tumors harboring NTRK fusions and were approved by FDA.

CASE PRESENTATION: We report a case of sarcoma in a 35-year-old female harboring two STRN-NTRK2 gene fusions, with a good clinical response to first-line larotrectinib treatment. Core biopsy of the 16.5 cm gluteal mass …

Emotional Barriers And Facilitators Of Deprescribing For Older Adults With Cancer And Polypharmacy: A Qualitative Study, Erika Ramsdale, Arul Malhotra, Holly M Holmes, Lisa Zubkoff, Jinjiao Wang, Supriya Mohile, Sally A Norton, Paul R Duberstein

Faculty, Staff and Student Publications

Purpose: To describe emotional barriers and facilitators to deprescribing (the planned reduction or discontinuation of medications) in older adults with cancer and polypharmacy.

Methods: Virtual focus groups were conducted over Zoom with 5 key informant groups: oncologists, oncology nurses, primary care physicians, pharmacists, and patients. All groups were video- and audio-recorded and transcribed verbatim. Focus group transcripts were analyzed using inductive content analysis, and open coding was performed by two coders. A codebook was generated based on the initial round of open coding and updated throughout the analytic process. Codes and themes were discussed for each transcript until consensus was …

Associations Between Birth Defects And Childhood And Adolescent Germ Cell Tumors According To Sex, Histologic Subtype, And Site, Jeremy M Schraw, Pagna Sok, Tania A Desrosiers, Amanda E Janitz, Peter H Langlois, Mark A Canfield, A Lindsay Frazier, Sharon E Plon, Philip J Lupo, Jenny N Poynter

Faculty, Staff and Students Publications

BACKGROUND: Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics.

METHODS: Birth defect-GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population-based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and …

Novobiocin Blocks Nucleic Acid Binding To Polθ And Inhibits Stimulation Of Its Atpase Activity, Aleem Syed, Frantisek Filandr, Jeffrey Patterson-Fortin, Albino Bacolla, Ramya Ravindranathan, Jia Zhou, Drew T Mcdonald, Mohammed E Albuhluli, Amy Verway-Cohen, Joseph A Newman, Miaw-Sheue Tsai, Darin E Jones, David C Schriemer, Alan D D'Andrea, John A Tainer

Faculty, Staff and Student Publications

Polymerase theta (Polθ) acts in DNA replication and repair, and its inhibition is synthetic lethal in BRCA1 and BRCA2-deficient tumor cells. Novobiocin (NVB) is a first-in-class inhibitor of the Polθ ATPase activity, and it is currently being tested in clinical trials as an anti-cancer drug. Here, we investigated the molecular mechanism of NVB-mediated Polθ inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational and cellular assays, we found NVB is a non-competitive inhibitor of ATP hydrolysis. NVB sugar group deletion resulted in decreased potency and reduced HX-MS interactions, supporting a specific NVB binding orientation. Collective results revealed that NVB …

Integrated Molecular Characterization Of Intraductal Papillary Mucinous Neoplasms: An Nci Cancer Moonshot Precancer Atlas Pilot Project, Alexander Semaan, Vincent Bernard, Justin Wong, Yuki Makino, Daniel B Swartzlander, Kimal I Rajapakshe, Jaewon J Lee, Adam Officer, Christian Max Schmidt, Howard H Wu, Courtney L Scaife, Kajsa E Affolter, Daniela Nachmanson, Matthew A Firpo, Michele Yip-Schneider, Andrew M Lowy, Olivier Harismendy, Subrata Sen, Anirban Maitra, Yasminka A Jakubek, Paola A Guerrero

Faculty, Staff and Student Publications

Intraductal papillary mucinous neoplasms (IPMN) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low-grade (LG) to high-grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN progression have been analyzed using multiregion sequencing for somatic mutations, there is no integrated assessment of molecular events, including copy-number alterations (CNA) and transcriptional changes that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histologic dysplasia obtained from 23 patients, followed by whole-exome and whole-transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with …

Outcomes Of Breakthrough Covid-19 Infections In Patients With Hematologic Malignancies, Kelly S Chien, Christine B Peterson, Elliana Young, Dai Chihara, Elizabet E Manasanch, Jeremy L Ramdial, Philip A Thompson

Faculty, Staff and Student Publications

Patients with hematologic malignancies have both an increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and higher morbidity/mortality. They have lower seroconversion rates after vaccination, potentially leading to inferior coronavirus disease 2019 (COVID-19) outcomes, despite vaccination. We consequently evaluated the clinical outcomes of COVID-19 infections in 243 vaccinated and 175 unvaccinated patients with hematologic malignancies. Hospitalization rates were lower in the vaccinated group when compared with the unvaccinated group (31.3% vs 52.6%). However, the rates of COVID-19-associated death were similar at 7.0% and 8.6% in vaccinated and unvaccinated patients, respectively. By univariate logistic regression, females, older patients, …

Dendritic Cells As Shepherds Of T Cell Immunity In Cancer, Mikael J Pittet, Mauro Di Pilato, Christopher Garris, Thorsten R Mempel

Faculty, Staff and Student Publications

In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses. Here, we review the current understanding of DC-T cell interactions at both priming and effector sites of immune responses. We place emerging …

Cancer Survivors’ Health Behaviors And Outcomes: A Population-Based Study Of Sexual And Gender Minorities, Ulrike Boehmer, Shine Chang, Nelson F Sanchez, Bill M Jesdale, Matthew B Schabath

Faculty, Staff and Student Publications

BACKGROUND: Most case-control studies compare cancer survivors with general population controls without considering sexual orientation or gender identity. This case-control analysis compared health risk behaviors and health outcomes among sexual and gender minority cancer survivors to those of matched sexual and gender minority participants without cancer (controls).

METHODS: Using data from the 2014-2021 Behavioral Risk Factor Surveillance System, a population-based sample of 4507 cancer survivors who self-identified as transgender, gay men, bisexual men, lesbian women, or bisexual women were 1:1 propensity score matched, using age at survey, race and ethnicity, marital status, education, access to health care, and US census …

Enzyme-Mediated Depletion Of Methylthioadenosine Restores T Cell Function In Mtap-Deficient Tumors And Reverses Immunotherapy Resistance, Donjeta Gjuka, Elio Adib, Kendra Garrison, Jianfeng Chen, Yuxue Zhang, Wenjiao Li, Daniel Boutz, Candice Lamb, Yuri Tanno, Amin Nassar, Talal El Zarif, Neil Kale, Mehrdad Rakaee, Tarek H Mouhieddine, Sarah Abou Alaiwi, Alexander Gusev, Thomas Rogers, Jianjun Gao, George Georgiou, David J Kwiatkowski, Everett Stone

Faculty, Staff and Student Publications

Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs T cell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of …

Views Of Adolescents And Young Adults With Cancer And Their Oncologists Toward Patients' Participation In Genomic Research, Amanda M Gutierrez, Jill O Robinson, Robin Raesz-Martinez, Isabel Canfield, Mary A Majumder, Sarah Scollon, Lauren R Desrosiers, Rebecca L Hsu, Wendy Allen-Rhoades, D Williams Parsons, Sharon E Plon, Amy L Mcguire, Janet Malek

Faculty, Staff and Students Publications

Purpose:

With increased use of genomic testing in cancer research and clinical care, it is important to understand the perspectives and decision-making preferences of adolescents and young adults (AYAs) with cancer and their treating oncologists.

Methods:

We conducted an interview substudy of the BASIC3 Study, which enrolled newly diagnosed cancer patients <18 years of age with assent. Of 32 young adults (YAs) with cancer who reached the age of majority (AOM; 18 years) while on study, 12 were successfully approached and all consented to study continuation at AOM. Of those, seven completed an interview. Patients' oncologists, who enrolled and participated in return of clinical genomic results, were also interviewed (n = 12). Interviews were transcribed, deidentified, and analyzed using thematic analysis.

Results:

YAs cited the possibility of helping others and advancing science as major reasons for their assent to initial study enrollment and their willingness to consent at AOM. YAs thought obtaining informed consent from research participants for …

Current Perspectives On Mass Spectrometry-Based Immunopeptidomics: The Computational Angle To Tumor Antigen Discovery, Bing Zhang, Michal Bassani-Sternberg

Faculty, Staff and Students Publications

Identification of tumor antigens presented by the human leucocyte antigen (HLA) molecules is essential for the design of effective and safe cancer immunotherapies that rely on T cell recognition and killing of tumor cells. Mass spectrometry (MS)-based immunopeptidomics enables high-throughput, direct identification of HLA-bound peptides from a variety of cell lines, tumor tissues, and healthy tissues. It involves immunoaffinity purification of HLA complexes followed by MS profiling of the extracted peptides using data-dependent acquisition, data-independent acquisition, or targeted approaches. By incorporating DNA, RNA, and ribosome sequencing data into immunopeptidomics data analysis, the proteogenomic approach provides a powerful means for identifying …

A Translational Blueprint For Developing Intraoperative Imaging Agents Via Radiopharmaceutical-Guided Drug Design, Teresa E Sullivan, Servando Hernandez Vargas, Sukhen C Ghosh, Solmaz Aghaamiri, Naruhiko Ikoma, Ali Azhdarinia

Faculty, Staff and Student Publications

Cancer imaging is a rapidly evolving field due to the discovery of novel molecular targets and the availability of corresponding techniques to detect them with high precision, accuracy, and sensitivity. Nuclear medicine is the most widely used molecular imaging modality and has a growing toolkit of clinically used radiopharmaceuticals that enable whole-body tumor visualization, staging, and treatment monitoring for a variety of tumors in a non-invasive manner. The need for similar imaging capabilities in the operating room has led to the emergence of fluorescence-guided surgery (FGS) as a powerful technique that gives surgeons unprecedented ability to distinguish tumors from healthy …