Immunology and Infectious Disease Commons^™

Immunogenicity And Efficacy Of A Rabies-Based Vaccine Against Highly Pathogenic Influenza H5n1 Virus, Nir Paran, Christoph Wirblich, Randy Albrecht, Leila Zabihi Diba, Alessandro Tarquinio, Drishya Kurup, Charalambos C. Solomides, Adolfo García-Sastre, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

The recent spillover of highly pathogenic influenza A/H5N1 (HPAI-H5N1) viruses to cattle, other mammals, and humans poses a major risk to animal and human health. Virus adaptation to new species highlights the need for effective vaccines for animals and humans. We recently developed a rabies virus-based H5 vaccine encoding the HPAI-H5 antigen and presenting it on the surface of the rabies virus particle. To test the immunogenicity and efficacy of the vaccine in eliciting systemic and mucosal immune response, we vaccinated mice intramuscularly or intranasally with either live or inactivated and adjuvanted vaccine. The vaccine elicited neutralizing antibodies against RABV …

Combined Glycoprotein Mutations In Rabies Virus Promote Astrocyte Tropism And Protective Cns Immunity In Mice, Mirjam Anna Rita Bertoune, Corinna Kolbe, Ann-Cathrin Werner, Maren Steinmetz, Bernhard Dietzschold, Eberhard Weihe

Department of Microbiology and Immunology Faculty Papers

Rabies virus (RABV) causes fatal encephalitis once it invades the central nervous system (CNS), and treatment options are extremely limited at this stage. We investigated the recombinant RABV variants SPBN, SPBNGA (glycoprotein substitution R333E), SPBNGAK (R333E plus N194K), SPBNGAS (R333E plus N194S), and TriGAS (three copies of the R333E/N194S glycoprotein). We evaluated their cellular tropism and immune activation in an intracerebral mouse infection model using immunohistochemistry and confocal immunofluorescence. SPBNGAK (R333E/N194K) resulted in mixed neuronal and astrocytic infection and lethal disease. In contrast, the R333E/N194S mutations in the GAS variants were associated with reduced neuronal infection and apparent astrocyte-restricted infection …

The Inside Scoop: Elucidating The Three-Way Relationship Between Schistosoma Mansoni, The Gut, And Vaccines, Mariam A. Mhanna

Biomedical Sciences Theses & Dissertations

Schistosomiasis is a neglected tropical disease that affects over 250 million people worldwide. This blood fluke infection burdens communities and areas with limited to no access to clean fresh water. When a host is exposed to cercariae, the infectious agent, in a body of water, it matures in the host’s circulation into adult female and male worms. Copulated adult worms migrate to the mesentery, in the case of Schistosoma mansoni, and produce eggs that can cross the intestinal barrier and get excreted in the feces to continue the lifecycle. The effects of S. mansoni infection on the host …

Mutation Of Smarca4 Induces Cancer Cell-Intrinsic Defects In The Enhancer Landscape And Resistance To Immunotherapy, Yawen Wang, Ismail M Meraz, Md Qudratullah, Sasikumar Kotagiri, Yanyan Han, Yuanxin Xi, Jing Wang, Kadir C Akdemir, Jack A Roth, Yonathan Lissanu

Faculty, Staff and Student Publications

Cancer genomic studies have identified frequent alterations in genes encoding components of the SWI/SNF chromatin remodeling complex, including SMARCA4 and ARID1A. Importantly, clinical reports indicate that SMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. In this study, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, models with SMARCA4 loss showed decreased response to anti-PD-1 immunotherapy associated with significantly reduced infiltration of dendritic cells and CD4+ T cells into the tumor microenvironment. SMARCA4 loss in tumor cells led to profound downregulation of STING1, IL1β, and …

Assessing Cancer Therapeutic Efficacy In Vivo Using [2h7]Glucose Deuterium Metabolic Imaging, Mario C Chang, Vinay R Malut, Rohit Mahar, Anna Rushin, Marc A Mcleod, Geraldine L Pierre, Indu R Malut, Stephen J Staklinski, Max E Glanz, Mukundan Ragavan, Gaurav Sharma, Manoj Madheswaran, Arshee Badar, Aparna D Rao, Brian K Law, Michael S Kilberg, James H P Collins, Vikram D Kodibagkar, James A Bankson, Ralph J Deberardinis, Matthew E Merritt

Faculty, Staff and Student Publications

Metabolic imaging produces powerful visual assessments of organ function in vivo. Current techniques can be improved by safely increasing metabolic contrast. The gold standard, 2-[18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging, is limited by radioactive exposure and sparse assessment of metabolism beyond glucose uptake and retention. Deuterium magnetic resonance imaging (DMRI) with [6,6-2H2]glucose is nonradioactive, achieves tumor metabolic contrast, but can be improved by enriched contrast from deuterated water (HDO) based imaging. Here, we developed a DMRI protocol employing [2H7]glucose. Imaging 2H-signal and measuring HDO production in tumor-bearing mice detected differential glucose utilization across baseline tumors, tumors treated with vehicle control or …

Inhibition Of Histone Methyltransferase Ezh2 For Immune Interception Of Colorectal Cancer In Lynch Syndrome, Charles M Bowen, Fahriye Duzagac, Abel Martel-Martel, Laura Reyes-Uribe, Mahira Zaheer, Jacklyn Thompson, Nan Deng, Ria Sinha, Soham Mazumdar, Melissa W Taggart, Abhinav K Jain, Elena Tosti, Winfried Edelmann, Krishna M Sinha, Eduardo Vilar

Faculty, Staff and Student Publications

Colorectal precancers in Lynch syndrome (LS) exhibit a distinct immune profile, presenting unique opportunities for developing immune-interception strategies to prevent carcinogenesis. Epigenetic modulation by EZH2 of immune-related genes is implicated in the carcinogenesis of different cancer types, including colorectal cancer. This study utilizes a mouse model of LS and ex vivo colonic organoids to assess the effects of the EZH2 inhibitor GSK503 on immune regulatory pathways, tumorigenesis, and epigenetic reprogramming. Our findings revealed that GSK503 significantly increased CD4+ and CD8+ T cells in both splenocytes and colonic mucosa of treated mice compared with controls. Additionally, a preventive dose of GSK503 …

Targeted Inhibition Of Aurora Kinase A Promotes Immune Checkpoint Inhibition Efficacy In Human Papillomavirus-Driven Cancers, Soma Ghosh, Madison P O'Hara, Pragya Sinha, Tuhina Mazumdar, Lacin Yapindi, Jagannadha K Sastry, Faye M Johnson

Faculty, Staff and Student Publications

Background: Human papillomavirus (HPV)-driven cancers include head and neck squamous cell carcinoma and cervical cancer and represent approximately 5% of all cancer cases worldwide. Standard-of-care chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICIs) are associated with adverse effects and limited responses in patients with HPV-driven cancers. The integration of targeted therapies with ICIs may improve outcomes. In a previous study, we demonstrated that Aurora kinase A (AURKA, Aurora A) inhibitors lead to apoptosis of human HPV-positive cancer cells in vitro and in vivo. Here, we explored the potential of Aurora A inhibition to enhance response to ICIs in immune-competent …

Depletion Of Adipose Stroma-Like Cancer-Associated Fibroblasts Potentiates Pancreatic Cancer Immunotherapy, Joseph Rupert, Alexes Daquinag, Yongmei Yu, Yulin Dai, Zhongming Zhao, Mikhail G Kolonin

Faculty, Staff and Student Publications

This study shows that populations of CAFs have distinct effects on pancreatic cancer progression and shows that depletion of CAFs expressing adipose markers potentiates tumor/metastasis suppression effects of immune checkpoint blockade.

Schistosoma Mansoni Infection Causes Consistent Changes To The Fecal Bacterial Microbiota Of Mice Across And Within Sites, Mariam A. Mhanna, David T. Gauthier, Lisa M. Shollenberger

Biological Sciences Faculty Publications

Eggs of Schistosoma mansoni are produced by adult female worms in mesenteries of infected hosts. Eggs can cross the intestinal barrier and form granulomas in the tissue or breach and exit the host through fecal excretion. These interactions may affect the host microbiome assemblages. Given the potential for schistosomal alteration of host gut microbiome and subsequent effects on the fecal bacterial composition, it is important to conduct controlled microbiome studies on model animals. While pursuing these studies, it is important to take into account the different conditions in which microbiome studies are conducted and their consequent impacts on variability and …

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 …

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 …

Immune Responses Of Neonatal (14-Day Old) And Adult (6 Weeks Old) Mice Lung And Spleen Cells To Gamma-Irradiated Mycobacterium Tuberculosis Stimulation, Oyinkansola F. Adeyemi

Biotechnology Theses

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health challenge, especially in vulnerable populations like neonates, whose immune systems are still developing. Understanding the immune responses to Mtb in neonates is critical for the development of better vaccine and treatment strategies. Building upon previous research from our laboratory, which demonstrated that γMtb stimulated neonatal mice (0, 3, and 7 days old) lung cells displayed distinct cytokine profiles and increased expansion of myeloid-derived suppressor cell subpopulations than adult mice lung cells. In the current study, we investigated age-dependent immune responses in 14-day-old (neonates) and 6-week-old (adults) mice. We found …

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 …

A Novel Lentiviral Vector-Based Approach To Generate Chimeric Antigen Receptor T Cells Targeting, Pappanaicken R Kumaresan, Sebastian Wurster, Karishma Bavisi, Thiago Aparecido Da Silva, Paul Hauser, Jordan Kinnitt, Nathaniel D Albert, Uddalak Bharadwaj, Sattva Neelapu, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Invasive aspergillosis (IA) is a common and deadly mold infection in immunocompromised patients. As morbidity and mortality of IA are primarily driven by poor immune defense, adjunct immunotherapies, such as chimeric antigen receptor (CAR) T cells, are direly needed. Here, we propose a novel approach to generate Aspergillus fumigatus (AF)-CAR T cells using the single-chain variable fragment domain of monoclonal antibody AF-269-5 and a lentiviral vector system. These cells successfully targeted mature hyphal filaments of representative clinical and reference AF isolates and elicited a potent release of cytotoxic effectors and type 1 T cell cytokines. Furthermore, AF-CAR T cells generated …

Monophosphoryl Lipid A-Based Adjuvant To Promote The Immunogenicity Of Multivalent Meningococcal Polysaccharide Conjugate Vaccines, Kishore Alugupalli

Department of Microbiology and Immunology Faculty Papers

Activation of the adaptive immune system requires the engagement of costimulatory pathways in addition to B and T cell Ag receptor signaling, and adjuvants play a central role in this process. Many Gram-negative bacterial polysaccharide vaccines, including the tetravalent meningococcal conjugate vaccines (MCV4) and typhoid Vi polysaccharide vaccines, do not incorporate adjuvants. The immunogenicity of typhoid vaccines is due to the presence of associated TLR4 ligands in these vaccines. Because the immunogenicity of MCV4 is poor and requires boosters, I hypothesized that TLR4 ligands are absent in MCV4 and that incorporation of a TLR4 ligand-based adjuvant would improve their immunogenicity. …

Btn1a1 Is A Novel Immune Checkpoint Mutually Exclusive To Pd-L1, Young-Seung Kim, Seung-Hoon Lee, Andrew H Park, Chunai Wu, Bong-Ki Hong, Hyunjin Jung, Steven H Lin, Stephen S Yoo

Faculty, Staff and Student Publications

BACKGROUND: While Programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) blockade is a potent antitumor treatment strategy, it is effective in only limited subsets of patients with cancer, emphasizing the need for the identification of additional immune checkpoints. Butyrophilin 1A1 (BTN1A1) has been reported to exhibit potential immunoregulatory activity, but its ability to function as an immune checkpoint remains to be systematically assessed, and the mechanisms underlying such activity have yet to be characterized.

METHODS: BTN1A1 expression was evaluated in primary tumor tissue samples, and its ability to suppress T-cell activation and T cell-dependent tumor clearance was examined. …

Safety, Efficacy And Determinants Of Response Of Allogeneic Cd19-Specific Car-Nk Cells In Cd19+ B Cell Tumors: A Phase 1/2 Trial, David Marin, Ye Li, Rafet Basar, Hind Rafei, May Daher, Jinzhuang Dou, Vakul Mohanty, Merve Dede, Yago Nieto, Nadima Uprety, Sunil Acharya, Enli Liu, Jeffrey Wilson, Pinaki Banerjee, Homer A Macapinlac, Christina Ganesh, Peter F Thall, Roland Bassett, Mariam Ammari, Sheetal Rao, Kai Cao, Mayra Shanley, Mecit Kaplan, Chitra Hosing, Partow Kebriaei, Loretta J Nastoupil, Christopher R Flowers, Sadie Mae Moseley, Paul Lin, Sonny Ang, Uday R Popat, Muzaffar H Qazilbash, Richard E Champlin, Ken Chen, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were …

Gamma Delta T Cells In Acute Myeloid Leukemia: Biology And Emerging Therapeutic Strategies, Adishwar Rao, Akriti Agrawal, Gautam Borthakur, Venkata Lokesh Battula, Abhishek Maiti

Faculty, Staff and Student Publications

γδ T cells play an important role in disease control in acute myeloid leukemia (AML) and have become an emerging area of therapeutic interest. These cells represent a minor population of T lymphocytes with intrinsic abilities to recognize antigens in a major histocompatibility complex-independent manner and functionally straddle the innate and adaptive immunity interface. AML shows high expression of phosphoantigens and UL-16 binding proteins that activate the Vδ2 and Vδ1 subtypes of γδ T cells, respectively, leading to γδ T cell-mediated cytotoxicity. Insights from murine models and clinical data in humans show improved overall survival, leukemia-free survival, reduced risk of …

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 …

Pd-1 Blockade In Combination With Dasatinib Potentiates Induction Of Anti-Acute Lymphocytic Leukemia Immunity, Paul Koller, Natalia Baran, Karine Harutyunyan, Antonio Cavazos, Saradhi Mallampati, Renee L Chin, Zhou Jiang, Xian Sun, Heng-Huan Lee, Jennifer L Hsu, Patrick Williams, Xuelin Huang, Michael A Curran, Mien-Chie Hung, Marina Konopleva

Faculty, Staff and Student Publications

Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism …

Antimicrobial Mitochondrial Reactive Oxygen Species Induction By Lung Epithelial Immunometabolic Modulation, Yongxing Wang, Vikram V Kulkarni, Jezreel Pantaleón García, Miguel M Leiva-Juárez, David L Goldblatt, Fahad Gulraiz, Lisandra Vila Ellis, Jichao Chen, Michael K Longmire, Sri Ramya Donepudi, Philip L Lorenzi, Hao Wang, Lee-Jun Wong, Michael J Tuvim, Scott E Evans

Faculty, Staff and Student Publications

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in …

Autotaxin Suppresses Cytotoxic T Cells Via Lpar5 To Promote Anti-Pd-1 Resistance In Non-Small Cell Lung Cancer, Jessica M Konen, B Leticia Rodriguez, Haoyi Wu, Jared J Fradette, Laura Gibson, Lixia Diao, Jing Wang, Stephanie Schmidt, Ignacio I Wistuba, Jianjun Zhang, Don L Gibbons

Faculty, Staff and Student Publications

Non-small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations are immunologically warm tumors with partial responsiveness to anti-PD-(L)1 blockade; however, most patients observe little or no durable clinical benefit. To identify novel tumor-driven resistance mechanisms, we developed a panel of KP murine lung cancer models with intrinsic resistance to anti-PD-1 and queried differential gene expression between these tumors and anti-PD-1-sensitive tumors. We found that the enzyme autotaxin (ATX), and the metabolite it produces, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors and that ATX directly modulated antitumor immunity, with its expression negatively correlating with total and …

The Hylefm Gene In Phylefm Of Enterococcus Faecium Is Not Required In Pathogenesis Of Murine Peritonitis, Victoria H Wu, Bryan S Yung, Farhoud Faraji, Robert Saddawi-Konefka, Zhiyong Wang, Alexander T Wenzel, Miranda J Song, Meghana S Pagadala, Lauren M Clubb, Joshua Chiou, Sanju Sinha, Marin Matic, Francesco Raimondi, Thomas S Hoang, Rebecca Berdeaux, Dario A A Vignali, Ramiro Iglesias-Bartolome, Hannah Carter, Eytan Ruppin, Jill P Mesirov, J Silvio Gutkind

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include EP2, EP4, A2AR, β1AR and β2AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs–DREADD to activate …

Inhibition Of Microsomal Prostaglandin E2 Synthase Reduces Collagen Deposition In Melanoma Tumors And May Improve Immunotherapy Efficacy By Reducing T-Cell Exhaustion, Yasunari Fukuda, Sun-Hee Kim, Matias A Bustos, Sung-Nam Cho, Jason Roszik, Jared K Burks, Hong Kim, Dave S B Hoon, Elizabeth A Grimm, Suhendan Ekmekcioglu

Faculty, Staff and Student Publications

The arachidonic acid pathway participates in immunosuppression in various types of cancer. Our previous observation detailed that microsomal prostaglandin E2 synthase 1 (mPGES-1), an enzyme downstream of cyclooxygenase 2 (COX-2), limited antitumor immunity in melanoma; in addition, genetic depletion of mPGES-1 specifically enhanced immune checkpoint blockade therapy. The current study set out to distinguish the roles of mPGES-1 from those of COX-2 in tumor immunity and determine the potential of mPGES-1 inhibitors for reinforcing immunotherapy in melanoma. Genetic deletion of mPGES-1 showed different profiles of prostaglandin metabolites from that of COX-2 deletion. In our syngeneic mouse model, mPGES-1-deficient cells exhibited …

A Highly Selective Humanized Ddr1 Mab Reverses Immune Exclusion By Disrupting Collagen Fiber Alignment In Breast Cancer, Junquan Liu, Huai-Chin Chiang, Wei Xiong, Victor Laurent, Samuel C Griffiths, Jasmin Dülfer, Hui Deng, Xiujie Sun, Y Whitney Yin, Wenliang Li, Laurent P Audoly, Zhiqiang An, Thomas Schürpf, Rong Li, Ningyan Zhang

Faculty, Staff and Student Publications

BACKGROUND: Immune exclusion (IE) where tumors deter the infiltration of immune cells into the tumor microenvironment has emerged as a key mechanism underlying immunotherapy resistance. We recently reported a novel role of discoidin domain-containing receptor 1 (DDR1) in promoting IE in breast cancer and validated its critical role in IE using neutralizing rabbit monoclonal antibodies (mAbs) in multiple mouse tumor models.

METHODS: To develop a DDR1-targeting mAb as a potential cancer therapeutic, we humanized mAb9 with a complementarity-determining region grafting strategy. The humanized antibody named PRTH-101 is currently being tested in a Phase 1 clinical trial. We determined the binding …

Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Wen Zheng, Martin W Lafleur, Sarah B Johnson, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe

Faculty, Staff and Student Publications

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and …

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 …

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. …

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: …