Medical Immunology Commons^™

Chick Embryo Chorioallantoic Membrane As A Platform For Assessing The In Vivo Efficacy Of Chimeric Antigen Receptor T-Cell Therapy In Solid Tumors, Allison J Nipper, Emilie A K Warren, Kershena S Liao, Hsuan-Chen Liu, Chieko Michikawa, Caroline E Porter, Gabrielle A Wells, Mariana Villanueva, Fabio Henrique Brasil Da Costa, Ratna Veeramachaneni, Hugo Villanueva, Masataka Suzuki, Andrew G Sikora

Faculty, Staff and Student Publications

The fertilized chicken egg chorioallantoic membrane (CAM), a highly vascularized membrane nourishing the developing embryo, also supports rapid growth of three-dimensional vascularized tumors from engrafted cells and tumor explants. Because murine xenograft models suffer limitations of time, cost, and scalability, we propose CAM tumors as a rapid, efficient screening tool for assessing anti-tumor efficacy of chimeric Ag receptor (CAR) T cells against solid tumors. We tested the efficacy of human epidermal growth factor receptor 2 (HER2)-specific CAR T cells against luminescent, HER2-expressing (FaDu, SCC-47) or HER2-negative (MDA-MB-468) CAM-engrafted tumors. Three days after tumor engraftment, HER2-specific CAR T cells were applied …

Novel Immunomodulatory Properties Of Adenosine Analogs Promote Their Antiviral Activity Against Sars-Cov-2, Giulia Monticone, Zhi Huang, Peter Hewins, Thomasina Cook, Oygul Mirzalieva, Brionna King, Kristina Larter, Taylor Miller-Ensminger, Maria D. Sanchez-Pino, Timothy P. Foster, Olga V. Nichols, Alistair J. Ramsay, Samarpan Majumder, Dorota Wyczechowska, Darlene Tauzier, Elizabeth Gravois, Judy S. Crabtree, Jone Garai, Li Li, Jovanny Zabaleta, Mallory T. Barbier, Luis Del Valle, Kellie A. Jurado, Lucio Miele

School of Medicine Faculty Publications

The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case …

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation In Melanoma: Impact Of Antibiotic Preconditioning On Microbiome And Immunity, Isabella C Glitza, Yongwoo David Seo, Christine N Spencer, Jennifer R Wortman, Elizabeth M Burton, Farah A Alayli, Christopher P Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R Cabanski, Matthew C Wong, Christine B Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher Mcchalicher, Emily Walsh, Michael T Tetzlaff, Omid Hamid, Patrick A Ott, Genevieve M Boland, Ryan J Sullivan, Kenneth F Grossmann, Nadim J Ajami, Theresa Lavallee, Matthew R Henn, Hussein A Tawbi, Jennifer A Wargo

Faculty, Staff and Student Publications

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate …

Viral Reprogramming Of Host Transcription Initiation, Nathan A. Ungerleider, Claire Roberts, Tina M. O’Grady, Trang T. Nguyen, Melody Baddoo, Jia Wang, Eman Ishaq, Monica Concha, Meggie Lam, Jordan Bass, Truong D. Nguyen, Nick Van Otterloo, Nadeeshika Wickramarachchige-Dona, Dorota Wyczechowska, Maria Morales, Tianfang Ma, Yan Dong, Erik K. Flemington

School of Medicine Faculty Publications

Viruses are master remodelers of the host cell environment in support of infection and virus production. For example, viruses typically regulate cell gene expression through modulating canonical cell promoter activity. Here, we show that Epstein Barr virus (EBV) replication causes ‘de novo’ transcription initiation at 29674 new transcription start sites throughout the cell genome. De novo transcription initiation is facilitated in part by the unique properties of the viral pre-initiation complex (vPIC) that binds a TATT[T/A]AA, TATA box-like sequence and activates transcription with minimal support by additional transcription factors. Other de novo promoters are driven by the viral transcription factors, …

Correction: Horne Et Al White Matter Correlates Of Domain-Specific Working Memory, Autumn Horne, Junhua Ding, Tatiana T Schnur, Randi C Martin

Faculty, Staff and Student Publications

In the original publication [...].

Macrophage Polarization And Colorectal Cancer Immune Checkpoint Protein Expression., Anne Macleod

Electronic Theses and Dissertations

The majority of patients with colorectal cancer do not respond to treatment with immunotherapy. Immunotherapy requires the expression of cell surface immune checkpoint proteins (e.g. PDL1) to exert its effect. Most (>85%) of colorectal cancers do not express these proteins and this contributes in part to the poor prognosis and survival in patients with advanced disease. The patients in which immunotherapy is a potential treatment option, are a genetic subtype known as mismatch repair deficient, and have demonstrated an excellent response to anti-PD-1/PDL1 immunotherapy. A key feature of mismatch repair deficient (MMRd) cancers is their immune cell rich tumor …

Kras Allelic Variants In Biliary Tract Cancers, Gordon Taylor Moffat, Zishuo Ian Hu, Funda Meric-Bernstam, Elisabeth Kathleen Kong, Dean Pavlick, Jeffrey S Ross, Karthikeyan Murugesan, Lawrence Kwong, Anaemy Danner De Armas, Anil Korkut, Milind Javle, Jennifer J Knox

Faculty, Staff and Student Publications

IMPORTANCE: Biliary tract cancers (BTCs) contain several actionable molecular alterations, including FGFR2, IDH1, ERBB2 (formerly HER2), and KRAS. KRAS allelic variants are found in 20% to 30% of BTCs, and multiple KRAS inhibitors are currently under clinical investigation.

OBJECTIVES: To describe the genomic landscape, co-sequence variations, immunophenotype, genomic ancestry, and survival outcomes of KRAS-mutated BTCs and to calculate the median overall survival (mOS) for the most common allelic variants.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective, multicenter, pooled cohort study obtained clinical and next-generation sequencing data from multiple databases between January 1, 2017, and December 31, 2022. These databases included Princess …

Synthetic Cationic Helical Polypeptides For The Stimulation Of Antitumour Innate Immune Pathways In Antigen-Presenting Cells, Daeyong Lee, Kristin Huntoon, Yifan Wang, Minjeong Kang, Yifei Lu, Seong Dong Jeong, Todd M Link, Thomas D Gallup, Yaqing Qie, Xuefeng Li, Shiyan Dong, Benjamin R Schrank, Adam J Grippin, Abin Antony, Jonghoon Ha, Mengyu Chang, Yi An, Liang Wang, Dadi Jiang, Jing Li, Albert C Koong, John A Tainer, Wen Jiang, Betty Y S Kim

Faculty, Staff and Student Publications

Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) …

Genetic And Serological Markers In Colorectal Cancer Surgery, Adrian Silaghi, Vlad Denis Constantin, Dragos Serban, Dragos Epistatu, Ioana Paunica, Daniela Gabriela Bălan, Laura Florentina Rebegea

Journal of Mind and Medical Sciences

Colon cancer is relatively asymptomatic in the early stages, the manifestations appearing and intensifying with the evolution of the disease, especially when associated with local and/or systemic complications. In such cases, surgical interventions are often emergency and involve more extensive operations (on metabolically and immune-stressed organisms), so that an early diagnosis (endoscopy, tumor markers, etc.) remains not only desirable but even a priority, especially in predisposed patients (genetic factors, lifestyle, etc.). As a consequence, the involvement of tumor markers in colon neoplasms has become more and more investigated in recent times. This review investigates the roles of serological and genetic …

Lncrna Impact On Regorafenib Resistance In Colorectal Cancer, Ricardo Pequeno Bracho, Kyle Doxtater, Dennis Kwabiah, Yamile Abuchard Anaya, Sophia Leslie, Mohammad Shabir Hussain, Manish Tripathi

Research Symposium

Cancer metastasis is one of the deadliest aspects of the disease, with about 90% of all cancer-related deaths due to its development at different sites within the body. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the United States, with 40-50% of all patients developing metastasis at some point during their fight with the disease. With the approval of Regorafenib for treating metastatic colorectal cancer, steps have been taken to combat metastasis in colorectal cancer. A vital aspect of the development of metastasis is the development of resistance to first-line chemotherapy. Regorafenib is an oral small-molecule …

Grb2 Stabilizes Rad51 At Reversed Replication Forks Suppressing Genomic Instability And Innate Immunity Against Cancer, Zu Ye, Shengfeng Xu, Yin Shi, Xueqian Cheng, Yuan Zhang, Sunetra Roy, Sarita Namjoshi, Michael A Longo, Todd M Link, Katharina Schlacher, Guang Peng, Dihua Yu, Bin Wang, John A Tainer, Zamal Ahmed

Faculty, Staff and Student Publications

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS-STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment …

Editorial: Reviews And Advances In The Molecular Mechanisms Of Breast Cancer, A. Redfern, V. Agarwal, Suresh Alahari

School of Medicine Faculty Publications

No abstract provided.

Antibody Profiling And Predictive Modeling Discriminate Between Kaposi Sarcoma And Asymptomatic Kshv Infection, Sydney J. Bennett, Dicle Yalcin, Sara R. Privatt, Owen Ngalamika, Salum J. Lidenge, John T. West, Charles Wood

School of Medicine Faculty Publications

Protein-level immunodominance patterns against Kaposi sarcoma-associated herpesvirus (KSHV), the aetiologic agent of Kaposi sarcoma (KS), have been revealed from serological probing of whole protein arrays, however, the epitopes that underlie these patterns have not been defined. We recently demonstrated the utility of phage display in high-resolution linear epitope mapping of the KSHV latency-associated nuclear antigen (LANA/ORF73). Here, a VirScan phage immunoprecipitation and sequencing approach, employing a library of 1,988 KSHV proteome-derived peptides, was used to quantify the breadth and magnitude of responses of 59 sub-Saharan African KS patients and 22 KSHV-infected asymptomatic individuals (ASY), and ultimately to support an application …

Epstein-Barr Virus-Based Prognostic Model In Nodular Sclerosis Classic Hodgkin Lymphoma, Chen Jiang, Li-Yun Huang, Ji-Hao Zhou, Zhi-Ming Li, Yu Wang, Shuo Li, Jian-Chang Fu, Qi-Tao Huang, Qin Yan, Yu-Yuan Huang, Min Zuo, Shimin Hu, Robert Peter Gale, Yang Liang, Jing-Ping Yun, Yu-Hua Huang

Faculty, Staff and Student Publications

The role of Epstein-Barr virus (EBV) in lymphoma cells of nodular sclerosis classic Hodgkin lymphoma (NScHL) is controversial. Our aim was to explore this and establish a clinically feasible model for risk stratification. We interrogated data from 542 consecutive subjects with NScHL receiving ABVD therapy and demonstrated EBV-infection in their lymphoma cells with EBV-encoded small RNAs (EBERs) in situ hybridization. Subjects were divided into training and validation datasets. As data from the training dataset suggested EBERs-positivity was the only independent prognostic factor for both progression-free survival (PFS) and overall survival (OS), we developed corresponding prognostic models based on it. Our …

Avaren-Fc, A Novel Immunotherapeutic, Recruits Nk Cells In B16f10 Melanoma Tumor Tissue, Sreevatsa Vemuri, Katarina Mayer, Nobuyuki Matoba

Posters-at-the-Capitol

Melanoma is the fifth most common cancer in the US, with limited effective immunotherapeutic options available for patients. Avaren-Fc (AvFc) is a novel experimental immunotherapeutic agent with a unique “lectibody” property. It is capable of targeting cancer cells through the selective recognition of high mannose glycans, which are aberrantly overrepresented on the surface of malignant cells. AvFc can interact with circulating effector immune cells equipped with Fc receptors, such as natural killer (NK) cells to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and kill cancer cells. Previous work has shown that AvFc effectively induces ADCC activity against B16F10 cancer cells in vitro …

Interactions Between Myeloid Cells And Neutrophil Extracellular Traps In Pancreatic Ductal Adenocarcinoma, Hillary Gabrielle Pratt

Graduate Theses, Dissertations, and Problem Reports (ETD)

The 5-year-survival rate for pancreatic ductal adenocarcinoma (PDAC) is only 12% due in part to a lack of therapeutic strategies that target the pathophysiology of the disease. The only known curative therapy is surgical resection of the PDAC tumor, but only 20% of patients are eligible at the time of presentation. To improve outcomes for patients, new therapeutic options are needed. The PDAC tumor microenvironment (TME) is uniquely fibrotic and hypoxic, which is in part driven by the immune cell composition in the TME. Myeloid cells are a prominent immune infiltrate within the PDAC TME, so these cells have been …

Assessment Of Appropriate Anticoagulation And Rates Of Bte In Ambulatory Oncology Patients Using A Validated Risk Assessment Model (Khorana Scote), David Page, Alan Su, Nikki Moxon, Staci Mellinger, Tracy L. Kelly, Katherine Lyon, Pharmd, Ian Ingram, Stephanie Matta, Pharmd, Bcop

Books, Presentations, Posters, Etc.

Abstract: Cancer associated venous thromboembolisms (VTE) are associated with higher health care resource utilization (number of hospitalizations, hospital length of stay, inpatient/outpatient medical services) and can complicate treatment of cancer. The Khorana Predictive Model for Chemotherapy-Associated VTE is a validated risk assessment model that determines a patient’s risk of developing VTEs and provides recommendations for starting prophylactic anticoagulation in ambulatory oncology patients. The Khorana Score is composed of various patient characteristics including site of primary cancer, prechemotherapy platelet count, hemoglobin level, prechemotherapy leukocyte count, and BMI. National Comprehensive Cancer Network (NCCN) supportive care guidelines recommend prophylactically starting an anticoagulant if …

Transcriptomics Analysis Reveals Potential Mechanisms Underlying Mitochondrial Dysfunction And T Cell Exhaustion In Astronauts’ Blood Cells In Space, Maria Moreno-Villanueva, Luis E Jimenez-Chavez, Stephanie Krieger, Liang-Hao Ding, Ye Zhang, Adriana Babiak-Vazquez, Mark Berres, Sandra Splinter, Kristen E Pauken, Brian C Schaefer, Brian E Crucian, Honglu Wu

Faculty, Staff and Student Publications

Introduction: The impact of spaceflight on the immune system and mitochondria has been investigated for decades. However, the molecular mechanisms underlying spaceflight-induced immune dysregulations are still unclear.

Methods: In this study, blood from eleven crewmembers was collected before and during International Space Station (ISS) missions. Transcriptomic analysis was performed in isolated peripheral blood mononuclear cells (PBMCs) using RNA-sequencing. Differentially expresses genes (DEG) in space were determined by comparing of the inflight to the preflight samples. Pathways and statistical analyses of these DEG were performed using the Ingenuity Pathway Analysis (IPA) tool.

Results: In comparison to pre-flight, a total of 2030 …

Tim/Tam Receptors: A Potential Biomarker For Predicting Sensitivity To Zika Virus-Induced Oncolysis In Non-Small Cell Lung Cancers, Shankari Somasekar

Honors Undergraduate Theses

Non-small cell lung cancers (NSCLC) constitute 80-85% of lung cancers and are the leading cause of cancer-related deaths globally. The most common cause is prolonged smoking. Current treatment options for NSCLC include surgery, radiation, chemotherapy, targeted drug therapy, and immunotherapy. Although these medications are effective in the short term, patients often face issues of drug resistance and debilitating side effects with prolonged use. Currently, the use of Zika virus (ZIKV) is being researched as a possible alternative treatment for cancer, which minimizes side effects and the risk of drug resistance. TIM/TAM proteins are identified as the putative ZIKV receptors on …

Translational And Oncologic Significance Of Tertiary Lymphoid Structures In Pancreatic Adenocarcinoma, Zachary Gao, Joseph Azar, Huili Zhu, Sophia Williams-Perez, Sung Wook Kang, Celia Marginean, Mark P Rubinstein, Shalini Makawita, Hyun-Sung Lee, E Ramsay Camp

Faculty, Staff and Students Publications

Pancreatic adenocarcinoma (PDAC) is an aggressive tumor with poor survival and limited treatment options. PDAC resistance to immunotherapeutic strategies is multifactorial, but partially owed to an immunosuppressive tumor immune microenvironment (TiME). However, the PDAC TiME is heterogeneous and harbors favorable tumor-infiltrating lymphocyte (TIL) populations. Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop within non-lymphoid tissue under chronic inflammation in multiple contexts, including cancers. Our current understanding of their role within the PDAC TiME remains limited; TLS are complex structures with multiple anatomic features such as location, density, and maturity that may impact clinical outcomes such as …

Faslpr Gene Dosage Tunes The Extent Of Lymphoproliferation And T Cell Differentiation In Lupus, Ritu Bohat, Xiaofang Liang, Yanping Chen, Chunyu Xu, Ningbo Zheng, Ashley Guerrero, Jiakai Hou, Roshni Jaffery, Nicholas A Egan, Yaxi Li, Yitao Tang, Esra Unsal, Adolfo Robles, Si Chen, Angela M Major, Hadil Elldakli, Sang-Hyuk Chung, Han Liang, M John Hicks, Yong Du, Jamie S Lin, Xiqun Chen, Chandra Mohan, Weiyi Peng

Faculty, Staff and Student Publications

Sle1 and Fas^lpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Fas^lpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Fas^lpr/+ (Sle1homo.lprhet) and compared it with B6.Fas^lpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Fas^lpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly …

Childhood And Adolescent Relapsed/Refractory Aggressive B-Cell Lymphomas With T(8;14) And Bcl2 Expression, Burkitt Lymphoma Versus Diffuse Large B-Cell Lymphoma: A Diagnostic Challenge, Fouad El Dana, Sofia Alexandra Garces Narvaez, Nader K El-Mallawany, Jennifer E Agrusa, Zoann E Dreyer, Andrea N Marcogliese, Mohamed Tarek Elghetany, Jyotinder N Punia, Chi Young Ok, Keyur P Patel, Dolores H Lopez-Terrada, Kevin E Fisher, Choladda V Curry

Faculty, Staff and Students Publications

We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as “DLBCL-NOS with MYC rearrangement” using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World …

Artificial Intelligence-Powered Discovery Of Small Molecules Inhibiting Ctla-4 In Cancer, Navid Sobhani, Dana Rae Tardiel-Cyril, Dafei Chai, Daniele Generali, Jian-Rong Li, Jonathan Vazquez-Perez, Jing Ming Lim, Rachel Morris, Zaniqua N Bullock, Aram Davtyan, Chao Cheng, William K Decker, Yong Li

Faculty, Staff and Students Publications

BACKGROUND/OBJECTIVES: Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4.

SUBJECTS/METHODS: In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the …

Timigp: An R Package To Depict The Tumor Microenvironment From Bulk Transcriptomics, Chenyang Li, Jianjun Zhang, Chao Cheng

Faculty, Staff and Students Publications

Exploring the clinical relevance of diverse immune cell types within the tumor microenvironment is pivotal for unraveling cancer intricacies and developing treatments. Here, we present a protocol for using tumor immune microenvironment illustration based on gene pairs, an R package to deduce cell-cell interactions, unveiling the association between immune cell relative abundance and patient prognoses from bulk gene expression and survival data. We describe steps for harnessing cell-type markers derived from single-cell RNA sequencing data to map the tumor immune microenvironment across a spectrum of cancer types. For complete details on the use and execution of this protocol, please refer …

Formate Supplementation Enhances Antitumor Cd8+ T-Cell Fitness And Efficacy Of Pd-1 Blockade, Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W Lafleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe

Faculty, Staff and Student Publications

UNLABELLED: The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for …

Enhanced Cd19 Activity In B Cells Contributes To Immunodeficiency In Mice Deficient In The Icf Syndrome Gene Zbtb24, Zhengzhou Ying, Swanand Hardikar, Joshua B Plummer, Tewfik Hamidi, Bin Liu, Yueping Chen, Jianjun Shen, Yunxiang Mu, Kevin M Mcbride, Taiping Chen

Faculty, Staff and Student Publications

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here, we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels …

Pediatric Hiv+ Kaposi Sarcoma Exhibits Clinical, Virological, And Molecular Features Different From The Adult Disease, Carolina Caro-Vegas, Alice Peng, Angelica Juarez, Allison Silverstein, William Kamiyango, Jimmy Villiera, Casey L Mcatee, Rizine Mzikamanda, Tamiwe Tomoka, Erin C Peckham-Gregory, Razia Moorad, Carrie L Kovarik, Liane R Campbell, Parth S Mehta, Peter N Kazembe, Carl E Allen, Michael E Scheurer, Nmazuo W Ozuah, Dirk P Dittmer, Nader Kim El-Mallawany

Center for Medical Ethics and Health Policy Staff Publications

BACKGROUND

Kaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.

METHODS

This was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were …

Highly Invasive Biliary Cancer Presenting As Multiple Extrabiliary Lesions Masquerading As Abscesses, Alexander Lu, Alireza Mojtahedi, Lukman Cheraghvandi, David Wynne, Neda Zarrin-Khameh, Mohammad Ghasemi Rad

Faculty, Staff and Students Publications

Carcinosarcomas of the biliary tract are an extremely rare type of malignancy and may be low on a differential when presenting as multiple metastatic masses. In this case report, we report a case of a female who presented with an aggressive late-stage disease whose initial workup did not indicate a malignant process. Further complicating her care, biopsy samples taken from extra-hepatic masses were culture-positive for Lactobacillus rhamnosu. Given the late stage of the patient’s disease, hospice care was initiated. The patient passed away four months after the initial presentation.

The Gut Microbiome As A Biomarker And Therapeutic Target In Hepatocellular Carcinoma, Betul Gok Yavuz, Saumil Datar, Shadi Chamseddine, Yehia I Mohamed, Michael Lapelusa, Sunyoung S Lee, Zishuo Ian Hu, Eugene J Koay, Hop S Tran Cao, Prasun Kumar Jalal, Carrie Daniel-Macdougall, Manal Hassan, Dan G Duda, Hesham M Amin, Ahmed O Kaseb

Faculty, Staff and Student Publications

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, …

Mir-146a Inhibits Ovarian Tumor Growth In Vivo Via Targeting Immunosuppressive Neutrophils And Enhancing Cd8+ T Cell Infiltration, Rui Chen, Elaina Coleborn, Chintan Bhavsar, Yue Wang, Louisa Alim, Andrew N Wilkinson, Michelle A Tran, Gowri Irgam, Sharat Atluri, Kiefer Wong, Jae-Jun Shim, Siddharth Adityan, Ju-Seog Lee, Willem W Overwijk, Raymond Steptoe, Da Yang, Sherry Y Wu

Faculty, Staff and Student Publications

Immunotherapies have emerged as promising strategies for cancer treatment. However, existing immunotherapies have poor activity in high-grade serous ovarian cancer (HGSC) due to the immunosuppressive tumor microenvironment and the associated low tumoral CD8+ T cell (CTL) infiltration. Through multiple lines of evidence, including integrative analyses of human HGSC tumors, we have identified miR-146a as a master regulator of CTL infiltration in HGSC. Tumoral miR-146a expression is positively correlated with anti-cancer immune signatures in human HGSC tumors, and delivery of miR-146a to tumors resulted in significant reduction in tumor growth in both ID8-p53−/− and IG10 murine HGSC models. Increasing miR-146a expression …