Immunology and Infectious Disease Commons^™

Fgl2-Targeting T Cells Exhibit Antitumor Effects On Glioblastoma And Recruit Tumor-Specific Brain-Resident Memory T Cells, Qingnan Zhao, Jiemiao Hu, Lingyuan Kong, Shan Jiang, Xiangjun Tian, Jing Wang, Rintaro Hashizume, Zhiliang Jia, Natalie Wall Fowlkes, Jun Yan, Xueqing Xia, Sofia F Yi, Long Hoang Dao, David Masopust, Amy B Heimberger, Shulin Li

Faculty, Staff and Student Publications

Although tissue-resident memory T (TRM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain TRM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)–specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8+ TRM cells that prevent glioblastoma recurrence. These CD8+ TRM cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8+ TRM cells reject glioma cells. Mechanistically, T-αFGL2 …

The Landscape Of Immunotherapy For Retroperitoneal Sarcoma, Alicia A Gingrich, Elise F Nassif, Christina L Roland, Emily Z Keung

Faculty, Staff and Student Publications

Significant multidisciplinary scientific effort has been undertaken to understand the heterogeneous family of neoplasms that comprise soft tissue sarcomas. Within this family of neoplasms, outcomes for retroperitoneal sarcomas (RPS) are currently limited given a lack of effective therapies. In this review, we focus on immunotherapy and its relationship with the common RPS histologic subtypes. Although initial outcomes for RPS patients with immune checkpoint inhibition alone have been somewhat disappointing, subsequent analyses on histologies, the tumor microenvironment, sarcoma immune class, tumor infiltrating lymphocytes and genetic analysis for tumor mutational burden have yielded insight into the interplay between sarcomas and immunotherapy. Such …

Probing Amyloid-Beta Protein Structure And Dynamics With A Selective Antibody, Shikha Grover

Dissertations

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. The AD brain is characterized by significant neuronal loss and accumulation of insoluble fibrillar amyloid-β protein (Aβ) plaques and tau protein neurofibrillary tangles in the brain. However, over the last decade, many studies have shown that the neurodegenerative effect of Aβ may in fact be caused by various soluble oligomeric forms as opposed to the insoluble fibrils. Furthermore, the data suggest that a pre-fibrillar aggregated form, termed protofibrils, mediates direct neurotoxicity, and triggers a robust neuroinflammatory response.

Antibodies targeting the various conformation of Aβ are important therapeutic agents to prevent the progression …

Pkr Induces Tgf-Β And Limits Oncolytic Immune Therapy, Bangxing Hong, Upasana Sahu, Matthew P Mullarkey, Evan Hong, Guangsheng Pei, Yuanqing Yan, Yoshihiro Otani, Yeshavanth Banasavadi-Siddegowda, Huihui Fan, Zhongming Zhao, Jianhua Yu, Michael A Caligiuri, Balveen Kaur

Faculty, Staff and Student Publications

BACKGROUND: Mammalian cells have developed multiple intracellular mechanisms to defend against viral infections. These include RNA-activated protein kinase (PKR), cyclic GMP-AMP synthase and stimulation of interferon genes (cGAS-STING) and toll-like receptor-myeloid differentiation primary response 88 (TLR-MyD88). Among these, we identified that PKR presents the most formidable barrier to oncolytic herpes simplex virus (oHSV) replication in vitro.

METHODS: To elucidate the impact of PKR on host responses to oncolytic therapy, we generated a novel oncolytic virus (oHSV-shPKR) which disables tumor intrinsic PKR signaling in infected tumor cells.

RESULTS: As anticipated, oHSV-shPKR resulted in suppression of innate antiviral immunity and improves virus …

Inhibition Of Myeloperoxidase Enhances Immune Checkpoint Therapy For Melanoma, Tracy W Liu, Seth T Gammon, Ping Yang, Wencai Ma, Jing Wang, David Piwnica-Worms

Faculty, Staff and Student Publications

BACKGROUND: The presence of a highly immunosuppressive tumor microenvironment has limited the success of immune checkpoint therapy (ICT). Immune suppressing myeloid cells with increased production of reactive oxygen species are critical drivers of this immunosuppressive tumor microenvironment. Strategies to limit these immune suppressing myeloid cells are needed to enhance response to ICT.

METHODS: To evaluate the contribution of myeloperoxidase (MPO), a myeloid lineage-restricted enzyme and a major source of reactive oxygen species, to mediating ICT response, we compared treatment outcome and immune composition in wild-type, MPO-deficient (

RESULTS: Tumor growth and survival studies demonstrated that either host deficiency (

CONCLUSION: …

Fucosylation Of Hla-Drb1 Regulates Cd4+ T Cell-Mediated Anti-Melanoma Immunity And Enhances Immunotherapy Efficacy, Daniel K Lester, Chase Burton, Alycia Gardner, Patrick Innamarato, Krithika Kodumudi, Qian Liu, Emma Adhikari, Qianqian Ming, Daniel B Williamson, Dennie T Frederick, Tatyana Sharova, Michael G White, Joseph Markowitz, Biwei Cao, Jonathan Nguyen, Joseph Johnson, Matthew Beatty, Andrea Mockabee-Macias, Matthew Mercurio, Gregory Watson, Pei-Ling Chen, Susan Mccarthy, Carlos Moransegura, Jane Messina, Kerry L Thomas, Lancia Darville, Victoria Izumi, John M Koomen, Shari A Pilon-Thomas, Brian Ruffell, Vincent C Luca, Robert S Haltiwanger, Xuefeng Wang, Jennifer A Wargo, Genevieve M Boland, Eric K Lau

Faculty, Staff and Student Publications

Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs); thus, effective strategies to safely increase itICs are needed. We report that dietary administration of l-fucose induces fucosylation and cell surface enrichment of the major histocompatibility complex (MHC)-II protein HLA-DRB1 in melanoma cells, triggering CD4+ T cell-mediated increases in itICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance …

Fibrinogen-Like Protein 2: Its Biological Function Across Cell Types And The Potential To Serve As An Immunotherapy Target For Brain Tumors, Sheng Zhang, Ganesh Rao, Amy Heimberger, Shulin Li

Faculty, Staff and Student Publications

Brain tumors are among the 10 leading causes of cancer-related death and present unique treatment challenges due to their critical location, genetic heterogeneity, and the blood-brain barrier. Recent advances in targeted immunotherapy and immune checkpoint blocking therapy provide alternative therapeutic strategies for brain tumors. Fibrinogen-like protein 2 (FGL2), which induces transformation from low-grade glioma to high-grade glioblastoma, is a type II membrane protein that is highly expressed in both host immune cells and tumor cells. Studies have uncovered multiple forms of FGL2 proteins with a broad range of roles in inducing immune tolerance and avoiding immune surveillance in tumor cells. …

Visualization And Characterization Of The Immunological Synapse Between Chlorotoxin Chimeric Antigen (Cltx-Car) Redirected T Cells And Targeted Glioblastoma Tumors, Arianna Livi

CMC Senior Theses

Chimeric Antigen Receptor T (CAR-T) cells have demonstrated anti-tumor activity against aggressive and invasive cancers such as glioblastoma (GBM); however, clinical response rates remain low in clinical trial studies. Tumor heterogeneity and tumor microenvironment conditions pose significant challenges for treatment of GBM, thus continuous optimization of CAR-T cell therapies and identification of novel, widely expressed, and highly specific GBM antigens are vital to better patient outcomes. A newly developed CAR-T cell construct incorporating chlorotoxin (CLTX) as the targeting domain exhibited broad GBM-targeting capabilities and elicited potent cytotoxic effects during preclinical studies and is currently being tested in a phase I …

What Costimulatory Domains In Chimeric Antigen Receptor T Cells Induce The Strongest Killing Response And Increase Serial Killing Efficacy Against Pediatric Rhabdomyosarcomas And Osteosarcomas?, Kristen Wilkins

Longwood Senior Thesis Proposal

No abstract provided.

Meta-Narrative Review Of Pd-L1 By Immunotherapy On Triple-Negative Breast Cancer, Hannah Lazo, Tyler Harris, Hao Truong, Alina Masroor

Research Methods Poster Session 2023

Triple-negative breast cancer (TNBC) is an aggressive form of subtype breast cancer and there are currently new treatments being discovered such as the combination of immunotherapy and chemotherapy. In immunotherapy against triple-negative breast cancer, checkpoint inhibitors like PD-1/PD-L1 treat TNBC by blocking the “off” signal that prevents T-cells from killing cancer cells. As a group, we conducted a meta-narrative review collecting results from primary sources such as clinical trials and human experimental studies to support our research question on how PD-L1 inhibitor treatments compare to other treatments in patients with TNBC. The review included articles searched from Embase, Pubmed, EMBASE, …

Localized Delivery Of Gm-Csf In The Regulation Of Breast Tumor Oxygen And Anti-Tumor Immunity Through Macrophages, Nicole E. Mihalik

Graduate Theses, Dissertations, and Problem Reports (ETD)

GM-CSF has been employed as an adjuvant to cancer immunotherapies in solid tumors due to its ability to drive immune stimulatory macrophages and other myeloid cells that promote anti-tumor responses. However, GM-CSF does not always exert immune stimulatory effects on myeloid cells, and sometimes even drives immune suppressive phenotypes. GM-CSF effects on myeloid cells and the tumor microenvironment (TME) appear to vary across dosages and even cancer types. However, an optimal dosing regimen for GM-CSF has yet to be determined to-date, and this is further complicated by the fact that GM-CSF is often administered via oncolytic viruses or tumor vaccines …

The Impact Of Hiv-1 Tat And Morphine On Spatial Distribution Of Drugs In The Brain., Austin M. Jones

Theses and Dissertations

Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, the central nervous system (CNS) remains affected by the virus. Approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND) or neuroHIV. Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, viral replication, and potentially altering the antiretroviral concentrations within the brain.

Using a transgenic mouse that expresses the HIV-1 Tat protein, we examined the effects of Tat and morphine on antiretroviral accumulation and distribution and the effects of Tat on morphine accumulation within the brain using infrared matrix-assisted laser desorption electrospray ionization with mass spectrometry imaging (IR-MALDESI-MSI). …

Age-Induced Changes In Anti-Tumor Immunity Alter The Tumor Immune Infiltrate And Impact Response To Immuno-Oncology Treatments, Suzanne I Sitnikova, Jennifer A Walker, Laura B Prickett, Michelle Morrow, Viia E Valge-Archer, Matthew J Robinson, Robert W Wilkinson, Simon J Dovedi

Faculty, Staff and Student Publications

INTRODUCTION: Immuno-oncology (IO) research relies heavily on murine syngeneic tumor models. However, whilst the average age for a cancer diagnosis is 60 years or older, for practical purposes the majority of preclinical studies are conducted in young mice, despite the fact that ageing has been shown to have a significant impact on the immune response.

METHODS: Using aged (60-72 weeks old) mice bearing CT26 tumors, we investigated the impact of ageing on tumor growth as well as the immune composition of the tumor and peripheral lymphoid organs.

RESULTS: We found many differences in the immune cell composition of both the …

Small Molecule Inhibitor Of Tau Self-Association In A Mouse Model Of Tauopathy: A Preventive Study In P301l Tau Jnpl3 Mice, Eliot J Davidowitz, Patricia Lopez, Heidy Jimenez, Leslie Adrien, Peter Davies, James G Moe

Faculty, Staff and Student Publications

Advances in tau biology and the difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for small molecule drug discovery for neurodegenerative diseases. Here, we evaluated OLX-07010, a small molecule inhibitor of tau self-association, for the prevention of tau aggregation. The primary endpoint of the study was statistically significant reduction of insoluble tau aggregates in treated JNPL3 mice compared with Vehicle-control mice. Secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. This study was performed in JNPL3 mice, which are representative of inherited forms of 4-repeat tauopathies with …

Autologous T Cell Therapy For Mage-A4+ Solid Cancers In Hla-A*02+ Patients: A Phase 1 Trial, David S Hong, Brian A Van Tine, Swethajit Biswas, Cheryl Mcalpine, Melissa L Johnson, Anthony J Olszanski, Jeffrey M Clarke, Dejka Araujo, George R Blumenschein, Partow Kebriaei, Quan Lin, Alex J Tipping, Joseph P Sanderson, Ruoxi Wang, Trupti Trivedi, Thejo Annareddy, Jane Bai, Stavros Rafail, Amy Sun, Lilliam Fernandes, Jean-Marc Navenot, Frederic D Bushman, John K Everett, Derin Karadeniz, Robyn Broad, Martin Isabelle, Revashnee Naidoo, Natalie Bath, Gareth Betts, Zohar Wolchinsky, Dzmitry G Batrakou, Erin Van Winkle, Erica Elefant, Armin Ghobadi, Amanda Cashen, Anne Grand'maison, Philip Mccarthy, Paula M Fracasso, Elliot Norry, Dennis Williams, Mihaela Druta, David A Liebner, Kunle Odunsi, Marcus O Butler

Faculty, Staff and Student Publications

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced …

Association Of Immune-Related Adverse Events With The Outcomes Of Immune Checkpoint Inhibitors In Patients With Dmmr/Msi-H Metastatic Colorectal Cancer, Vincenzo Nasca, Francesco Barretta, Francesca Corti, Sara Lonardi, Monica Niger, Maria Elena Elez, Marwan Fakih, Priya Jayachandran, Aakash Tushar Shah, Massimiliano Salati, Elisabetta Fenocchio, Lisa Salvatore, Chiara Cremolini, Javier Ros, Margherita Ambrosini, Giacomo Mazzoli, Rossana Intini, Michael J Overman, Rosalba Miceli, Filippo Pietrantonio

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs.

METHODS: We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a 'burden score' constructed in a way that the same score value could be obtained by …

Targeting Immunosuppressive Ly6c+ Classical Monocytes Reverses Anti-Pd-1/Ctla-4 Immunotherapy Resistance, B Leticia Rodriguez, Limo Chen, Yanli Li, Shucheng Miao, David H Peng, Jared J Fradette, Lixia Diao, Jessica M Konen, Frank R Rojas Alvarez, Luisa M Solis, Xiaohui Yi, Aparna Padhye, Laura A Gibson, Joshua K Ochieng, Xiaofei Zhou, Jing Wang, Don L Gibbons

Faculty, Staff and Student Publications

Introduction: Despite significant clinical advancement with the use of immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) there are still a major subset of patients that develop adaptive/acquired resistance. Understanding resistance mechanisms to ICB is critical to developing new therapeutic strategies and improving patient survival. The dynamic nature of the tumor microenvironment and the mutational load driving tumor immunogenicity limit the efficacy to ICB. Recent studies indicate that myeloid cells are drivers of ICB resistance. In this study we sought to understand which immune cells were contributing to resistance and if we could modify them in a way …

Loss Of Ubiquitin-Specific Peptidase 18 Destabilizes 14-3-3Ζ Protein And Represses Lung Cancer Metastasis, Zibo Chen, Lin Zheng, Yulong Chen, Xiuxia Liu, Masanori Kawakami, Lisa Maria Mustachio, Jason Roszik, Katherine V Ferry-Galow, Ralph E Parchment, Xin Liu, Thorkell Andresson, Gerard Duncan, Jonathan M Kurie, Jaime Rodriguez-Canales, Xi Liu, Ethan Dmitrovsky

Faculty, Staff and Student Publications

Cancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered reduction of USP18 expression repressed lung cancer growth and promoted apoptosis. This deubiquitinase (DUB) stabilized targeted proteins by removing the complex interferon-stimulated gene 15 (ISG15). This study explores if the loss of USP18 reduced lung cancer metastasis. USP18 knock-down in lung cancer cells was independently achieved using small hairpin RNAs (shRNAs) and small interfering RNAs (siRNAs). USP18 knock-down reduced …

The Role Of Lncrnas In The Tumor Microenvironment And Immunotherapy Of Melanoma, Wencheng Zhou, Xuewen Xu, Ying Cen, Junjie Chen

Faculty, Staff and Student Publications

Melanoma is one of the most lethal tumors with highly aggressive and metastatic properties. Although immunotherapy and targeted therapy have certain therapeutic effects in melanoma, a significant proportion of patients still have drug resistance after treatment. Recent studies have shown that long noncoding RNAs (lncRNAs) are widely recognized as regulatory factors in cancer. They can regulate numerous cellular processes, including cell proliferation, metastasis, epithelial-mesenchymal transition (EMT) progression and the immune microenvironment. The role of lncRNAs in malignant tumors has received much attention, whereas the relationship between lncRNAs and melanoma requires further investigation. Our review summarizes tumor suppressive and oncogenic lncRNAs …

Nanofabrication For Precision Vaccinology, Karen Zagorski

Theses & Dissertations

Vaccines are among the most effective and safe therapeutics known to mankind. Historically the approach to the creation of new vaccines has been dominated by empirical research, trial, and error. This thesis focuses on the more modern, rational approaches to vaccinology based on the current understanding of the inner workings of the immune system. We used nanotechnology for the generation of novel immunogens, addressed several challenges, and characterized the immune responses.

The preparation, characterization, and troubleshooting of several vaccines against dimeric amyloid beta are covered in chapters 4-6. Despite being ultimately unsuccessful, this part provided a deeper understanding of the …

Screening Anti-Pd-L2 Peptides As Antitumor Ligands Using Phage Display, Chien Tran Phuoc

Honors Projects

Cancer still remains one of the top leading causes of death in America. Recently, programmed cell death protein 1 (PD-1) blockades have been demonstrated to be highly effective against various types of cancer. By blocking PD-1 from binding with their ligands (PD-L1 and PD-L2), the “off” signal to the immune system is inhibited, hence reinvigorating the immune cells to kill tumor cells. To date, despite PD-L1 and PD-L2 both interacting with PD-1, research efforts have only been focused on developing anti-PD-L1 inhibitors. Therefore, the work of this honor project has focused on finding anti-PD-L2 peptides by phage display, with the …

Understanding And Targeting The Immunosuppressive Tumor Microenvironment, Li Cai, Li Cai

Dissertations and Theses (Open Access)

Immune checkpoint inhibitors (ICIs), such as anti-PD1/PD-L1 and anti-CTLA-4, have shown impressive antitumor efficacy by improving the activity of T cells. While these inhibitors work in many patients with various cancer types, they have minimal or no effect in many more patients. Mounting evidence indicates that, besides current known immune checkpoints, other immunosuppressive components in the tumor microenvironment (TME) need to be targeted to elicit the full immune responses.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immunosuppressive myeloid cells that are involved in cancer progression and therapeutic resistance. In this work, we demonstrated the essential role of MDSCs …

Activated B Cells Suppress T-Cell Function Through Metabolic Competition, Nobuhiko Imahashi, Rafet Basar, Yuefan Huang, Fang Wang, Natalia Baran, Pinaki Prosad Banerjee, Junjun Lu, Ana Karen Nunez Cortes, Nadima Uprety, Emily Ensley, Luis Muniz-Feliciano, Tamara J Laskowski, Judy S Moyes, May Daher, Mayela Mendt, Lucila N Kerbauy, Mayra Shanley, Li Li, Francesca Lorraine Wei Inng Lim, Hila Shaim, Ye Li, Marina Konopleva, Michael Green, Jennifer Wargo, Elizabeth J Shpall, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

BACKGROUND: B cells play a pivotal role in regulating the immune response. The induction of B cell-mediated immunosuppressive function requires B cell activating signals. However, the mechanisms by which activated B cells mediate T-cell suppression are not fully understood.

METHODS: We investigated the potential contribution of metabolic activity of activated B cells to T-cell suppression by performing in vitro experiments and by analyzing clinical samples using mass cytometry and single-cell RNA sequencing.

RESULTS: Here we show that following activation, B cells acquire an immunoregulatory phenotype and promote T-cell suppression by metabolic competition. Activated B cells induced hypoxia in T cells …

Immunological Conversion Of Solid Tumours Using A Bispecific Nanobioconjugate For Cancer Immunotherapy, Yifei Lu, Kristin Huntoon, Daeyong Lee, Yifan Wang, Jonghoon Ha, Yaqing Qie, Xuefeng Li, Benjamin R Schrank, Shiyan Dong, Thomas D Gallup, Minjeong Kang, Hai Zhao, Yi An, Zhaogang Yang, Jing Li, Betty Y S Kim, Wen Jiang

Faculty, Staff and Student Publications

Solid tumours display a limited response to immunotherapies. By contrast, haematological malignancies exhibit significantly higher response rates to immunotherapies as compared with solid tumours. Among several microenvironmental and biological disparities, the differential expression of unique immune regulatory molecules contributes significantly to the interaction of blood cancer cells with immune cells. The self-ligand receptor of the signalling lymphocytic activation molecule family member 7 (SLAMF7), a molecule that is critical in promoting the body's innate immune cells to detect and engulf cancer cells, is expressed nearly exclusively on the cell surface of haematologic tumours, but not on solid ones. Here we show …

Spinal Metastases And The Evolving Role Of Molecular Targeted Therapy, Chemotherapy, And Immunotherapy, Elena I Fomchenko, James C Bayley, Christopher Alvarez-Breckenridge, Laurence D Rhines, Claudio E Tatsui

Faculty, Staff and Student Publications

Metastatic involvement of the spine is a common complication of systemic cancer progression. Surgery and external beam radiotherapy are palliative treatment modalities aiming to preserve neurological function, control pain and maintain functional status. More recently, with development of image guidance and stereotactic delivery of high doses of conformal radiation, local tumor control has improved; however recurrent or radiation refractory disease remains a significant clinical problem with limited treatment options. This manuscript represents a narrative overview of novel targeted molecular therapies, chemotherapies, and immunotherapy treatments for patients with breast, lung, melanoma, renal cell, prostate, and thyroid cancers, which resulted in improved …

Investigating The Pi3k/Akt/Atm Pathway, Telomeric Dna Damage, T Cell Death, And Crispr/Cas9-Mediated Gene Editing During Acute And Chronic Hiv Infection, Sushant Khanal

Electronic Theses and Dissertations

Human Immunodeficiency Virus (HIV) infection initiates major metabolic and cell- survival complications. Anti-retroviral therapy (ART) is the current approach to suppress active HIV replication to a level of undetected viral load, but it is not a curative approach. Newer and sophisticated gene editing technologies could indeed be a potent antiviral therapy to achieve a clinical sterilization/cure of HIV infection. Chronic HIV patients, even under a successful ART regimen, exhibit a low-grade inflammation, immune senescence, premature aging, telomeric DNA attrition, T cell apoptosis, and cellular homeostasis. In this dissertation, we investigated CD4 T cell homeostasis, degree of T cell apoptosis, an …

Tumor-Intrinsic Sirpa Promotes Sensitivity To Checkpoint Inhibition Immunotherapy In Melanoma, Zhicheng Zhou, Mei-Ju May Chen, Yikai Luo, Kamalika Mojumdar, Xin Peng, Hu Chen, Shweta V Kumar, Rehan Akbani, Yiling Lu, Han Liang

Faculty, Staff and Student Publications

Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. Here we perform integrative transcriptomic and proteomic analyses on emerging immuno-oncology targets across multiple clinical cohorts of melanoma under anti-PD-1 treatment, on both bulk and single-cell levels. We reveal a surprising role of tumor-intrinsic SIRPA in enhancing antitumor immunity, in contrast to its well-established role as a major inhibitory immune modulator in macrophages. The loss of SIRPA expression is a marker of melanoma dedifferentiation, a key phenotype linked to immunotherapy efficacy. Inhibition of SIRPA in melanoma cells abrogates tumor killing by activated CD8+ T cells in a co-culture …

Immune Dysfunction Signatures Predict Outcomes And Define Checkpoint Blockade-Unresponsive Microenvironments In Acute Myeloid Leukemia, Sergio Rutella, Jayakumar Vadakekolathu, Francesco Mazziotta, Stephen Reeder, Tung-On Yau, Rupkatha Mukhopadhyay, Benjamin Dickins, Heidi Altmann, Michael Kramer, Hanna A Knaus, Bruce R Blazar, Vedran Radojcic, Joshua F Zeidner, Andrea Arruda, Bofei Wang, Hussein A Abbas, Mark D Minden, Sarah K Tasian, Martin Bornhäuser, Ivana Gojo, Leo Luznik

Faculty, Staff and Student Publications

Background

Immune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like CD8⁺ T cells and whether they have prognostic relevance.

METHODS

We analyzed NanoString, bulk RNA-Seq and single-cell RNA-Seq data from independent clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB).

Results

We show that senescent-like bone marrow CD8⁺ T cells were impaired in killing autologous AML blasts and that their proportion negatively correlated with overall survival …

T Cells Specific For Α-Myosin Drive Immunotherapy-Related Myocarditis, Margaret L Axelrod, Wouter C Meijers, Elles M Screever, Juan Qin, Mary Grace Carroll, Xiaopeng Sun, Elie Tannous, Yueli Zhang, Ayaka Sugiura, Brandie C Taylor, Ann Hanna, Shaoyi Zhang, Kaushik Amancherla, Warren Tai, Jordan J Wright, Spencer C Wei, Susan R Opalenik, Abigail L Toren, Jeffrey C Rathmell, P Brent Ferrell, Elizabeth J Phillips, Simon Mallal, Douglas B Johnson, James P Allison, Javid J Moslehi, Justin M Balko

Faculty, Staff and Student Publications

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, …

Using The Embl-Ebi Clustal Omega Tool To Calculate Diversity Of Heavy Chain Phage-Display Libraries, Michael Bodri, Shane A. Webb

Georgia Journal of Science

Here we show that traditional Sanger sequencing combined with analysis tools available from the European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), specifically EMBOSS Transeq and Clustal Omega, is extremely effective in the analysis of naïve phage display antibody libraries for the determination of library size and diversity. The free tools are easy to use and require little manipulation of reads by hand, allowing analysis to be performed on a standard personal computer. Utilization of this technique has applicability to researchers with limited access to deep sequencing. The primary drawback to this analysis methodology is that antibodies with particular molecular or …