Hsa-Mir-214-3p Inhibits Breast Cancer Cell Growth And Improves The Tumor Immune Microenvironment By Downregulating B7h3, Yan Lu, Kang Wang, Yuanhong Peng, Meng Chen, Lin Zhong, Luji Huang, F U Cheng, Xindan Sheng, Xin Yang, Manzhao Ouyang, George A Calin, Zhiwei He

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint inhibitors play an important role in the treatment of solid tumors, but the currently used immune checkpoint inhibitors targeting programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) show limited clinical efficacy in many breast cancers. B7H3 has been widely reported as an immunosuppressive molecule, but its immunological function in breast cancer patients remains unclear.

METHODS: We analyzed the expression of B7H3 in breast cancer samples using data from the Cancer Genome Atlas Program (TCGA) and the Gene Expression Omnibus (GEO) databases. MicroRNAs were selected using the TarBase, miRTarBase, and miRBase databases. …

Timigp: A Computational Framework To Determine The Tumor Immune Microenvironment Associated With Prognosis And Immunotherapy Response, Chenyang Li

Dissertations and Theses (Open Access)

Accumulating evidence has suggested that the tumor immune microenvironment (TIME) drastically impacts cancer patients’ clinical outcomes, including prognosis and immunotherapy response. However, understanding TIME remains challenging due to its complexity and heterogeneity. In this dissertation, we introduce TimiGP (Tumor Immune Microenvironment Illustration based on Gene Pairs), a computational framework designed to address this challenge. Leveraging single-cell RNA-seq (scRNA-seq) and bulk gene expression data alongside clinical information, TimiGP constructs a cell-cell interaction network that elucidates the relationship between immune cell function and relevant clinical outcomes, such as prognosis and treatment response. With immunological insights, these cell-cell interactions also facilitate the development …

The Role Of Lifr Signaling In Innate Immunity, Laura Kahn Serrudo

Dissertations and Theses (Open Access)

The localized signals that bone marrow (BM) hematopoietic stem cells (HSCs) and immune cells receive are critical in regulating their responses in the steady state and inflammation. Monocytes are an abundant and key population in the innate immune response that originates in the BM, and they circulate to monitor the periphery. Monocytes are composed of many subsets that have essential and specific functions, including swift egress from the BM, production of pro-inflammatory cytokines, and differentiation into monocyte-derived dendritic cells (MoDCs), which are required for efficient pathogen eradication.

Here, we uncovered LIFR (leukemia inhibitory factor receptor) restrains low-grade chronic inflammation in …

Oncolytic Viruses Enhance Long-Term Nk Cell Anti-Tumor Cytotoxicity Through Ap-1 And Irf Pathway Activation, Xin Ru Jiang

Dissertations and Theses (Open Access)

Natural killer (NK) cell therapeutics have emerged as a promising strategy in adoptive cellular therapy. While genetic modifications of NK cells can enhance their antitumor activity, modulating the tumor to augment NK cell recognition and function remains underexplored. In this study, we investigated the combination of NK cells with oncolytic viruses to treat solid tumors, specifically pancreatic ductal adenocarcinoma and glioblastoma. We demonstrated that infecting tumor cells with the oncolytic adenovirus Delta-24-RGD significantly increases their susceptibility to NK cell cytotoxicity, driven by a hyperactivated NK cell phenotype characterized by elevated expression of activating receptors and cytotoxicity markers. In a patient-derived …

Local Or Systemic Antibody-Targeted Sting Activation Drives Pro- Inflammatory Stromal Metabolic Changes And Downregulates C-Myc Oncoprotein, Akash Boda

Dissertations and Theses (Open Access)

The past decade has witnessed remarkable advances in the field of cancer immunotherapy. Immune checkpoint blockade (ICB) has emerged as a cornerstone, achieving long-lasting tumor regression in several types of cancer. However, its effectiveness is often limited, particularly in certain tumor types. Immunologically "cold" tumors, such as pancreatic ductal adenocarcinoma (PDAC), remain clinically unresponsive to ICB, presenting a significant challenge in oncology. Amidst these challenges, the stimulation of the STING pathway via small molecule synthetic agonists has surfaced as a promising strategy. Acting as an in-situ vaccine, STING activation has the potential to transform the immune landscape of cold tumors …

The Role Of Ganglioside Gd2 And Gd3 Synthase (St8sia1) In The Regulation Of Immune Suppression In Breast Cancer, Bolutyfe Oderinde

Dissertations and Theses (Open Access)

Gangliosides are acidic glycosphingolipids involved in cell adhesion, proliferation, and modulation of signal transduction pathways. It has been reported that tumor-shed gangliosides influence the activity of immune cells including macrophages, NK cells, and T cells. GD3 synthase (GD3S) is the key enzyme that regulates the biosynthesis of the b and c series gangliosides, particularly GD3 and GD2, and studies have shown that GD3S is upregulated in most tumors and plays a role in tumor progression. Similarly, we have previously found GD3S to be significantly upregulated in GD2+ breast cancer stem cells (BCSC) compared to GD2- cells, and the knockdown of …

Systematic Review Of Immune Checkpoint Inhibitor-Related Gastrointestinal, Hepatobiliary, And Pancreatic Adverse Events, Malek Shatila, Hao Chi Zhang, Anusha Shirwaikar Thomas, Antonio Pizuorno Machado, Sidra Naz, Nitish Mittal, Christine Catinis, Krishnavathana Varatharajalu, Carolina Colli Cruz, Eric Lu, Deanna Wu, Julie R Brahmer, Franck Carbonnel, Stephen B Hanauer, Bret Lashner, Bryan Schneider, John A Thompson, Michel Obeid, David P Farris, Yinghong Wang

Faculty, Staff and Student Publications

Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity …

Circulating Galectin-3: A Prognostic Biomarker In Hepatocellular Carcinoma, Shadi Chamseddine, Betul Gok Yavuz, Yehia I Mohamed, Sunyoung S Lee, James C Yao, Zishuo Ian Hu, Michael Lapelusa, Lianchun Xiao, Ryan Sun, Jeffrey S Morris, Rikita I Hatia, Manal Hassan, Dan G Duda, Maria Diab, Amr Mohamed, Ahmed Nassar, Hesham M Amin, Ahmed Omar Kaseb

Faculty, Staff and Student Publications

INTRODUCTION: Galectin-3 plays critical roles in the adhesion, proliferation, and differentiation of tumor cells. Recent data have suggested that galectin-3 plays a role in the development of hepatocellular carcinoma (HCC); however, its prognostic value has not been validated. The aim of our study was to evaluate the clinical and prognostic value of galectin-3 in patients with HCC.

METHODS: We prospectively enrolled and collected clinicopathologic data and serum samples from 767 patients with HCC between 2001 and 2014 at The University of Texas MD Anderson Cancer Center. Two hundred patients without HCC were also enrolled and had data collected. The Kaplan-Meier …

Diaphragmatic Myopathy Associated With Dual Immune Checkpoint Inhibitors In A Patient With Renal Cell Carcinoma, Jeremy R Walder, Saadia A Faiz, Sudhakar Tummala, Shiao-Pei Weathers, Nicolas L Palaskas, Maryam Buni, Ajay Sheshadri, Lara Bashoura

Faculty, Staff and Student Publications

Immune-related adverse events (irAEs) have become increasingly prevalent with immune checkpoint inhibitor (ICI) cancer treatment. We present a 79-year-old man with metastatic renal cell carcinoma who developed shortness of breath and hypercapnic respiratory insufficiency after his first cycle of nivolumab and ipilimumab. Laboratory data showed elevated creatinine kinase, troponins, and transaminases. Computed tomography of the chest demonstrated bilateral lower lobe atelectasis. Heart catheterization and endomyocardial biopsy were unremarkable. Electromyogram (EMG) and nerve conduction studies (NCS) of the limb muscles revealed mild diffuse myopathy, normal sensory nerve conductions, and low-amplitude motor responses. Subsequent diaphragmatic EMG and NCS demonstrated severe myopathy. ICI-mediated …

Type I Met Inhibitors Cooperate With Pd-1 Blockade To Promote Rejection Of Hepatocellular Carcinoma, Ricardo Deazevedo, Madeline Steiner, Broderick X Turner, Arthur Liu, Sherwin Newton, Joanna Schmidt, Rachel Fleming, Angelica Tolentino, Ahmed O Kaseb, Michael A Curran

Faculty, Staff and Student Publications

Blockade of the immune checkpoints programmed death-1 (PD-1) and cytotoxic lymphocyte antigen 4 has improved outcomes for patients with hepatocellular carcinoma (HCC), yet most still fail to achieve objective clinical benefit. MET plays key roles in both HCC tumorigenesis and immunosuppressive conditioning; however, inhibition of MET causes upregulation of PD-ligand 1 (PD-L1) suggesting the use of these inhibitors in the context of PD-1 blockade. We sought to investigate across the Hepa1-6, HCA-1 and diethylnitrosamine (DEN) models of HCC whether the combination of more specific type I versus more pleiotropic type II MET inhibitors would confer superior outcomes in combination with …

Impact Of Select Actionable Genomic Alterations On Efficacy Of Neoadjuvant Immunotherapy In Resectable Non-Small Cell Lung Cancer, Nicolas Zhou, Cheuk H Leung, William N William, Annikka Weissferdt, Apar Pataer, Myrna C B Godoy, Brett W Carter, Frank V Fossella, Anne S Tsao, George R Blumenschein, Xiuning Le, Jianjun Zhang, Ferdinandos Skoulidis, Jonathan M Kurie, Mehmet Altan, Charles Lu, Bonnie S Glisson, Lauren A Byers, Yasir Y Elamin, Reza J Mehran, David C Rice, Garrett L Walsh, Wayne L Hofstetter, Jack A Roth, Hai T Tran, Jia Wu, Luisa M Solis Soto, Humam Kadara, Stephen G Swisher, Ara A Vaporciyan, Don L Gibbons, Heather Y Lin, J Jack Lee, John V Heymach, Marcelo V Negrao, Boris Sepesi, Tina Cascone

Faculty, Staff and Student Publications

Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant ICIs remains unclear. We report the influence of AGAs on treatment failure (TF) in patients with resectable NSCLC treated with neoadjuvant ICIs.

Methods: Tumor molecular profiles were obtained from patients with stage I-IIIA resectable NSCLC (American Joint Committee on Cancer seventh edition) treated with either neoadjuvant nivolumab (N, n=23) or nivolumab+ipilimumab (NI, n=21) followed by surgery in a previously reported phase-2 randomized study (NCT03158129). TF …

Perioperative Chemoimmunotherapy Induces Strong Immune Responses And Long-Term Survival In Patients With Hla Class I-Deficient Non-Small Cell Lung Cancer, Marta Molina-Alejandre, Francisco Perea, Virginia Calvo, Cristina Martinez-Toledo, Ernest Nadal, Belén Sierra-Rodero, Marta Casarrubios, Joaquín Casal-Rubio, Alex Martinez-Martí, Amelia Insa, Bartomeu Massuti, Santiago Viteri, Isidoro Barneto Aranda, Delvys Rodriguez-Abreu, Javier De Castro, Joaquín Mosquera Martínez, Manuel Cobo, Ignacio I Wistuba, Edwin R Parra, Javier Martín-López, Diego Megías, Rafael Muñoz-Viana, Federico Garrido, Natalia Aptsiauri, Francisco Ruiz-Cabello, Mariano Provencio, Alberto Cruz-Bermúdez

Faculty, Staff and Student Publications

BACKGROUND: Loss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy. However, there is no data on perioperative chemoimmunotherapy (ChIO) efficacy or response mechanisms in the context of HLA class I defects.

METHODS: Baseline HLA class I tumor status (HLA-deficient (HLA-DEF) or HLA-proficient (HLA-PRO)) was determined by DNA LOH combined with immunohistochemistry for protein levels in tissue of 24 patients with NSCLC treated with perioperative nivolumab plus chemotherapy from NADIM trial (NCT03081689). We integrated HLA tumor status with molecular data …

Tcellsi: A Novel Method For T Cell State Assessment And Its Applications In Immune Environment Prediction, Jing-Min Yang, Nan Zhang, Tao Luo, Mei Yang, Wen-Kang Shen, Zhen-Lin Tan, Yun Xia, Libin Zhang, Xiaobo Zhou, Qian Lei, An-Yuan Guo

Faculty, Staff and Student Publications

T cell is an indispensable component of the immune system and its multifaceted functions are shaped by the distinct T cell types and their various states. Although multiple computational models exist for predicting the abundance of diverse T cell types, tools for assessing their states to characterize their degree of resting, activation, and suppression are lacking. To address this gap, a robust and nuanced scoring tool called T cell state identifier (TCellSI) leveraging Mann-Whitney

Mta-Cooperative Prmt5 Inhibitors Enhance T Cell-Mediated Antitumor Activity In Mtap-Loss Tumors, Si Chen, Jiakai Hou, Roshni Jaffery, Ashley Guerrero, Rongjie Fu, Leilei Shi, Ningbo Zheng, Ritu Bohat, Nicholas A Egan, Chengtai Yu, Sana Sharif, Yue Lu, Wei He, Shuyue Wang, Donjeta Gjuka, Everett M Stone, Pooja Anil Shah, Jordi Rodon Ahnert, Taiping Chen, Xinli Liu, Mark T Bedford, Han Xu, Weiyi Peng

Faculty, Staff and Student Publications

BACKGROUND: Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer.

METHODS: Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were …

Comprehensive Investigation Into The Molecular Mechanisms Driving The Emergence Of Emm4 Group A Streptococcus, Chioma Odo, Samuel A Shelburne, Anthony R. Flores, Steven J Norris, Anna Konovalova, Blake Hanson

Dissertations and Theses (Open Access)

Abstract

Comprehensive Investigation into the Molecular Mechanisms Driving the Emergence of emm4 Group A Streptococcus

Chioma Modeline Odo, M.S.

Advisory Professor: Samuel A. Shelburne, MD, Ph.D.

The major gram-positive bacterium group A Streptococcus (GAS) is a model organism for studying microbial epidemics as it is well known to cause infections that occur in waves. GAS strains are grouped based on the composition of the N-terminal sequence of the M protein which is encoded by the emm gene. With the advent of large-scale whole genome sequencing, GAS clonal emergence events in emm1, emm3, and emm89 types have been identified …

Tsyn-Seq: A T Cell Synapse-Based Antigen Identification Platform, Yimei Jin

Dissertations and Theses (Open Access)

Tools for genome-wide rapid identification of peptide–major histocompatibility complex targets of T-cell receptors (TCRs) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APCs) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell–APC aggregates were detected by dual reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 …

The Role Of An Ultraconserved Long Non-Coding Rna In B-Cell Lymphomagenesis, Swati Mohapatra

Dissertations and Theses (Open Access)

Ultraconserved regions (UCRs) are genomic segments with perfect (100%) conservation between the orthologous regions of human, rat, and mouse genomes. UCRs can be transcribed into mono-exonic long non-coding RNAs (lncRNAs) known as transcribed ultraconserved regions (T-UCRs). These regions, despite lacking protein-coding potential, are increasingly recognized for their regulatory roles in gene expression, including the modulation of non-coding RNA (ncRNA) transcripts. NcRNAs play crucial roles in cellular processes, including oncogenic transformation, with emerging evidence revealing their ability to encode small peptides known as ncRNA-encoded peptides (ncPEPs). These peptides, originating from small open reading frames (smORFs), contribute to diverse cellular functions and …

Real-World Evidence Study On The Early Use Of Cemiplimab In The Uk: React-Cemi (Real World Evidence Of Advanced Cscc Treatment With Cemiplimab), Amarnath Challapalli, Grant Stewart, Heather Shaw, Peter John Davies, Juan Carlos Lopez-Baez, Edward C Ottley, Stephen Kelly

Faculty, Staff and Student Publications

BACKGROUND: Cemiplimab was licensed in the United Kingdom (UK) in 2019 for the treatment of patients with locally advanced and metastatic CSCC not suitable for curative surgery or radiotherapy (advanced CSCC [aCSCC]). No UK multi-center studies have investigated the real-world experience of cemiplimab post marketing authorization in aCSCC.

METHODS: This non-interventional retrospective study (10 UK centers) involved data collection from medical records of patients with aCSCC who initiated cemiplimab treatment between 2 July 2019 and 30 November 2020. The study period was a minimum of 12 and a maximum of 36 months post cemiplimab initiation. The primary objective was to …

The Multifaceted Role Of Neutrophils In Nsclc In The Era Of Immune Checkpoint Inhibitors, Shucheng Miao, Bertha Leticia Rodriguez, Don L Gibbons

Faculty, Staff and Student Publications

Lung cancer is the most common cause of cancer-related death in both males and females in the U.S. and non-small-cell lung cancer (NSCLC) accounts for 85%. Although the use of first- or second-line immune checkpoint inhibitors (ICIs) exhibits remarkable clinical benefits, resistance to ICIs develops over time and dampens the efficacy of ICIs in patients. Tumor-associated neutrophils (TANs) have an important role in modulating the tumor microenvironment (TME) and tumor immune response. The major challenge in the field is to characterize the TANs in NSCLC TME and understand the link between TAN-related immunosuppression with ICI treatment response. In this review, …

Challenges And Opportunities In Cancer Immunotherapy: A Society For Immunotherapy Of Cancer (Sitc) Strategic Vision, Leisha A Emens, Pedro J Romero, Ana Carrizosa Anderson, Tullia C Bruno, Christian M Capitini, Deborah Collyar, James L Gulley, Patrick Hwu, Avery D Posey, Ann W Silk, Jennifer A Wargo

Faculty, Staff and Student Publications

Cancer immunotherapy has flourished over the last 10-15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge. For example, advances in technologies such as single-cell sequencing and spatial transcriptomics have provided deep insights into the immunobiology of the tumor …

The Role Of Micrornas On Systemic And Central Nervous System- Inflammation In Aged Mice, Anik Banerjee

Dissertations and Theses (Open Access)

MicroRNAs play a crucial role in multiple biological processes, including development, cell differentiation, proliferation, metabolism, and cell death. Aberrant regulation of microRNAs is seen in many diseases, such as sepsis, cardiovascular disease, neurological diseases such as stroke, and metabolic disorders. Because of their involvement in disease processes, microRNAs have been investigated as both potential biomarkers, and as therapeutic targets. Age-related inflammatory diseases including diabetes, obesity, and atherosclerosis are important risk factors for infection and sepsis. Intestinal barrier impairment occurs with aging and after brain injuries, including stroke. Both aging and stroke increase the risk of infection and sepsis and are …

Targeting Sinonasal Undifferentiated Carcinoma With A Combinatory Immunotherapy Approach, Austin T K Hoke, Yoko Takahashi, Michelle R Padget, Javier Gomez, Moran Amit, Jared Burks, Diana Bell, Tongxin Xie, Patrick Soon-Shiong, James W Hodge, Ehab Y Hanna, Nyall R London

Faculty, Staff and Student Publications

PURPOSE: Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy of the sinonasal cavity with poor prognosis and limited treatment options. To investigate the potential for SNUC sensitivity to combinatory immunotherapy, we performed in vitro studies with SNUC cell lines and used multi-spectral immunofluorescence to characterize the in vivo patient SNUC tumor immune microenvironment (TIME).

EXPERIMENTAL DESIGN: Human-derived SNUC cell lines were used for in vitro studies of tumor cell susceptibility to natural killer (NK) cell-based immunotherapeutic strategies. Tumor samples from 14 treatment naïve SNUC patients were examined via multi-spectral immunofluorescence and clinical correlations assessed.

RESULTS: Anti-PD-L1 blockade enhanced NK …

Developing A Membrane-Proximal Cd33-Targeting Car T Cell, Ruby Freeman, Sanam Shahid, Abdul G Khan, Serena C Mathew, Sydney Souness, Erin R Burns, Jasmine S Um, Kento Tanaka, Winson Cai, Sarah Yoo, Andrew Dunbar, Young Park, Devin Mcavoy, Kinga K Hosszu, Ross L Levine, Jaap Jan Boelens, Ivo C Lorenz, Renier J Brentjens, Anthony F Daniyan

Faculty, Staff and Student Publications

BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.

METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.

RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both …

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 [...].

Kras G12c Inhibitor Combination Therapies: Current Evidence And Challenge, Hirotaka Miyashita, Shumei Kato, David S Hong

Faculty, Staff and Student Publications

Although KRAS G12C inhibitors have proven that KRAS is a "druggable" target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical …

Mismatch Repair Deficient Neoantigen And Associated Circulating T-Cell Receptor Repertoires In Lynch Syndrome, Ana Bolivar

Dissertations and Theses (Open Access)

Lynch Syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome. It constitutes the perfect model to understand DNA mismatch repair deficient (MMRd) carcinogenesis, which underlies 15% of early-stage CRC. LS patients develop MMRd tumors with high loads of shared neoantigens (neoAgs), which are recognized by the immune system. Previous research has concentrated on discovering neoAgs and their potential as targets for vaccines in LS patients. However, these studies have primarily identified shared neoAgs from cancers, lacking detailed information on targetable neoAgs present in precancerous lesions. Understanding this landscape of pre-cancer derived neoAgs is crucial for intercepting cancer development …

Oxidative Phosphorylation In Melanoma Brain Metastases: A Regulator Of The Tumor Immune Landscape, Renato A. Guerrieri

Dissertations and Theses (Open Access)

Previously, we demonstrated via RNA-sequencing analysis of murine intracranial melanoma tumors that pharmacologic inhibition of oxidative phosphorylation (OXPHOS) results in increased expression of genes consistent with activated anti-tumor immune responses. The central hypothesis of this dissertation is that OXPHOS plays a critical role in the pathogenesis and immune regulation of melanoma brain metastases (MBMs).

The functional significance of OXPHOS was assessed through genetic inhibition, involving knockout (KO) of key regulatory genes such as Ppargc1a (PGC1a) and Ndfus4 (NDUFS4), a component of mitochondrial complex I. PGC1a KO in an RCAS-TVA mouse model of autochthonous lung and brain tumors developing from primary …

The Role Of Anti-Viral Immune Response On The Therapeutic Efficacy Of Oncolytic Virotherapy For High-Grade Gliomas, Dong Ho Shin Phd

Dissertations and Theses (Open Access)

Currently, there is no effective treatment for high-grade gliomas that are resistant to conventional treatments and immune checkpoint blockade therapies. Oncolytic viruses offer a new treatment modality by selectively replicating in cancer cells and inducing anti-tumor immunity. Among these viruses, the oncolytic adenovirus Delta-24-RGD has shown safety and efficacy in clinical trials for high-grade gliomas. Strategies to improve the efficacy of oncolytic virotherapy have aimed to heighten the immunogenicity of oncolytic viruses, either by incorporating immune-stimulating transgenes or by combining treatments with immune checkpoint blockades. However, such strategies may inadvertently trigger heightened immune responses to viral antigens, which may not …

Loss Of Ptdss1 In Tumor Cells Improves Anti-Pd-1 Therapy, Jielin Liu

Dissertations and Theses (Open Access)

PTDSS1 (Phosphatidylserine synthase 1) encodes an enzyme that facilitates production of phosphatidylserine (PS), which mediates a global immunosuppressive signal. Here, based on in vivo CRISPR screen, we identified PTDSS1 as a target to improve anti-PD-1 therapy. Depletion of PTDSS1 in tumor cells increased expression of IFNγ-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1. Loss of PTDSS1 in tumor cells also led to increased expression of MHC-I, which was associated with increased expression of cytolytic function related genes in CD8⁺ T cells and increased frequency of an iNOS⁺ myeloid subset. A gene signature derived from the iNOS⁺ myeloid …

Exploring The Role Of Il-1Β/Il-1r In The Pathogenesis Of K-Ras Mutant Lung Cancer, Avantika Krishna

Dissertations and Theses (Open Access)

As the leading cause of cancer-related deaths worldwide, the development of targeted therapeutics to treat lung cancer remains crucial. Non-small cell lung cancer (NSCLC), the most common histological subtype predominantly comprises lung adenocarcinoma with driver mutations in the K-ras oncogene (KM-LUAD). KM-LUAD progression partly occurs through activation of the NF-κB pathway initiating an inflammatory response and creating a pro-tumor microenvironment. Notably, the pro-inflammatory cytokine IL-1β a potent activator and product of the NF-κB pathway is elevated in the lungs and sera of KM-LUAD patients. We have shown that IL-1β blockade promotes an anti-tumor immune phenotype in a mouse model of …