Biomedical Informatics Commons^™

Global Research Trends And Prospects Related To Tumor Microenvironment Within Triple Negative Breast Cancer: A Bibliometric Analysis, Peiting Li, Jun Li, Xiaofei Tong, Zhenyang Xiao, Wuliang Diao, Chi Zhong, Jianda Zhou, Wei Wu

Faculty, Staff and Student Publications

Background and aims: The tumor microenvironment (TME) has pivotal parts within multiple tumor models of onset/progression, such as triple-negative breast cancer (TNBC). This bibliometric analysis was developed to explore trends and research niches revolving around TME in TNBC.

Methods: Web of Science Core Collection was queried for identifying studies linked with TME in TNBC, after which the VOSviewer, CiteSpace, and R software programs were used to conduct bibliometric analyses and to generate corresponding visualizations.

Results: In total, this study included 1,604 studies published from 2005-2023. The USA and China exhibited the highest numbers of citations, and the research institutions with …

A Bibliometric And Visual Analysis Of Cancer-Associated Fibroblasts, Wei-Chen Yuan, Jie-Xiang Zhang, Hai-Bin Chen, Ying Yuan, Yu-Pei Zhuang, Hong-Li Zhou, Mu-Han Li, Wen-Li Qiu, Hong-Guang Zhou

Faculty, Staff and Student Publications

Background: Cancer-associated fibroblasts (CAFs) represent the predominant stromal component within the tumour microenvironment (TME), exhibiting considerable heterogeneity and plasticity that significantly impact immune response and metabolic reprogramming within the TME, thereby influencing tumour progression. Consequently, investigating CAFs is of utmost importance. The objective of this study is to employ bibliometric analysis in order to evaluate the current state of research on CAFs and predict future areas of research and emerging trends.

Methods: Conduct a comprehensive search for scholarly publications within the Web of Science Core Collection database, encompassing the time period from January 1, 2001, to December 31, 2022. Apply …

Radiotherapy Reimagined: Integrating Nanomedicines Into Radiotherapy Clinical Trials, Allison N Duross, Jack Phan, Alexander J Lazar, Joshua M Walker, Alexander R Guimaraes, Carole Baas, Sunil Krishnan, Charles R Thomas, Conroy Sun, Alexander F Bagley

Faculty, Staff and Student Publications

Radioenhancing nanoparticles (NPs) are being evaluated in ongoing clinical trials for various cancers including head and neck, lung, esophagus, pancreas, prostate, and soft tissue sarcoma. Supported by decades of preclinical investigation and recent randomized trial data establishing clinical activity, these agents are poised to influence future multimodality treatment paradigms involving radiotherapy. Although the physical interactions between NPs and ionizing radiation are well characterized, less is known about how these agents modify the tumor microenvironment, particularly regarding tumor immunogenicity. In this review, we describe the key multidisciplinary considerations related to radiation, surgery, immunology, and pathology for designing radioenhancing NP clinical trials. …

The Interplay Between Neoantigens And Immune Cells In Sarcomas Treated With Checkpoint Inhibition, Irantzu Anzar, Brandon Malone, Pubudu Samarakoon, Ioannis Vardaxis, Boris Simovski, Hugues Fontenelle, Leonardo A Meza-Zepeda, Richard Stratford, Emily Z Keung, Melissa Burgess, Hussein A Tawbi, Ola Myklebost, Trevor Clancy

Faculty, Staff and Student Publications

INTRODUCTION: Sarcomas are comprised of diverse bone and connective tissue tumors with few effective therapeutic options for locally advanced unresectable and/or metastatic disease. Recent advances in immunotherapy, in particular immune checkpoint inhibition (ICI), have shown promising outcomes in several cancer indications. Unfortunately, ICI therapy has provided only modest clinical responses and seems moderately effective in a subset of the diverse subtypes.

METHODS: To explore the immune parameters governing ICI therapy resistance or immune escape, we performed whole exome sequencing (WES) on tumors and their matched normal blood, in addition to RNA-seq from tumors of 31 sarcoma patients treated with pembrolizumab. …

Il-8 Produced Via Bidirectional Communication Between Prostate Cancer And M2 Macrophages As A Potential Diagnostic And Prognostic Biomarker, Huihui Fan, Zheng Tang, Yaling Tian, Qingsong Lv, Fangyin Zeng

Faculty, Staff and Student Publications

PURPOSE: Owing to the mortality associated with metastatic prostate cancer and the shortcomings of the current parameters in predicting the disease prognosis, we require the identification of viable biomarkers, which would help in the diagnosis and prognosis of the disease. We aimed to determine whether the interleukin-8 level in the tumor microenvironment could serve as a potential clinical diagnostic marker and prognostic factor for prostate cancer.

METHODS: The migration assay of prostate cancer cells was performed in an in vitro co-culture model. Cell lines PC3 and DU145 were divided into two groups and co-cultured with M0 and M2 macrophages, respectively. …

A Th2-Score In The Tumor Microenvironment As A Predictive Biomarker Of Response To Bacillus Calmette Guérin In Patients With Non-Muscle Invasive Bladder Carcinoma: A Retrospective Study, Gustavo Martín Villoldo, María Teresa Pombo, Mariana Aris, Joaquín Chemi, Pablo Mandó, Supriya Nagaraju, Juan Camean, Adrián Burioni, Deborah Egea, Mora Amat, José León Mellado, José Mordoh, Alberto Villaronga, María Marcela Barrio

Faculty, Staff and Student Publications

Intravesical Bacillus Calmette Guerin (BCG) is the gold standard therapy for intermediate/high-risk non-muscle invasive bladder cancer (NMIBC). However, the response rate is ~60%, and 50% of non-responders will progress to muscle-invasive disease. BCG induces massive local infiltration of inflammatory cells (Th1) and ultimately cytotoxic tumor elimination. We searched for predictive biomarker of BCG response by analyzing tumor-infiltrating lymphocyte (TIL) polarization in the tumor microenvironment (TME) in pre-treatment biopsies. Pre-treatment biopsies from patients with NMIBC who received adequate intravesical instillation of BCG (n = 32) were evaluated retrospectively by immunohistochemistry. TME polarization was assessed by quantifying the T-Bet+ (Th1) and GATA-3+ …

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 …

Spatial Heterogeneity Of Infiltrating T Cells In High-Grade Serous Ovarian Cancer Revealed By Multi-Omics Analysis, Bin Yang, Xiong Li, Wei Zhang, Junpeng Fan, Yong Zhou, Wenting Li, Jingjing Yin, Xiaohang Yang, Ensong Guo, Xi Li, Yu Fu, Si Liu, Dianxing Hu, Xu Qin, Yingyu Dou, Rourou Xiao, Funian Lu, Zizhuo Wang, Tianyu Qin, Wei Wang, Qinghua Zhang, Shuaicheng Li, Ding Ma, Gordon B Mills, Gang Chen, Chaoyang Sun

Faculty, Staff and Student Publications

Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, represent a favorable prognostic factor in high-grade serous ovarian cancer (HGSOC) and other tumor lineages. Here, we analyze the spatial heterogeneity of different TIL subtypes in HGSOC. We integrated RNA sequencing, whole-genome sequencing, bulk T cell receptor (TCR) sequencing, as well as single-cell RNA/TCR sequencing to investigate the characteristics and differential composition of TILs across different HGSOC sites. Two immune "cold" patterns in ovarian cancer are identified: (1) ovarian lesions with low infiltration of mainly dysfunctional T cells and immunosuppressive Treg cells and (2) omental lesions infiltrated with non-tumor-specific bystander cells. Exhausted CD8 T …

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 …

Egfr Is A Master Switch Between Immunosuppressive And Immunoactive Tumor Microenvironment In Inflammatory Breast Cancer, Xiaoping Wang, Takashi Semba, Ganiraju C Manyam, Jing Wang, Shan Shao, Francois Bertucci, Pascal Finetti, Savitri Krishnamurthy, Lan Thi Hanh Phi, Troy Pearson, Steven J Van Laere, Jared K Burks, Evan N Cohen, James M Reuben, Fei Yang, Hu Min, Nicholas Navin, Van Ngu Trinh, Toshiaki Iwase, Harsh Batra, Yichao Shen, Xiang Zhang, Debu Tripathy, Naoto T Ueno

Faculty, Staff and Student Publications

Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype, is driven by an immunosuppressive tumor microenvironment (TME). Current treatments for IBC have limited efficacy. In a clinical trial (NCT01036087), an anti-EGFR antibody combined with neoadjuvant chemotherapy produced the highest pathological complete response rate ever reported in patients with IBC having triple-negative receptor status. We determined the molecular and immunological mechanisms behind this superior clinical outcome. Using novel humanized IBC mouse models, we discovered that EGFR-targeted therapy remodels the IBC TME by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages. These changes were due to …

Defining Cellular Population Dynamics At Single-Cell Resolution During Prostate Cancer Progression, Alexandre A Germanos, Sonali Arora, Ye Zheng, Erica T Goddard, Ilsa M Coleman, Anson T Ku, Scott Wilkinson, Hanbing Song, Nicholas J Brady, Robert A Amezquita, Michael Zager, Annalysa Long, Yu Chi Yang, Jason H Bielas, Raphael Gottardo, David S Rickman, Franklin W Huang, Cyrus M Ghajar, Peter S Nelson, Adam G Sowalsky, Manu Setty, Andrew C Hsieh

Faculty, Staff and Student Publications

Advanced prostate malignancies are a leading cause of cancer-related deaths in men, in large part due to our incomplete understanding of cellular drivers of disease progression. We investigate prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in an in vivo murine model. We observe an expansion of a castration-resistant intermediate luminal cell type that correlates with treatment resistance and poor prognosis in human patients. Moreover, transformed epithelial cells and associated fibroblasts create a microenvironment conducive to pro-tumorigenic immune infiltration, which is partially androgen responsive. Androgen-independent prostate cancer leads to significant diversification of …

Mapping Single-Cell Transcriptomes In The Intra-Tumoral And Associated Territories Of Kidney Cancer, Ruoyan Li, John R Ferdinand, Kevin W Loudon, Georgina S Bowyer, Sean Laidlaw, Francesc Muyas, Lira Mamanova, Joana B Neves, Liam Bolt, Eirini S Fasouli, Andrew R J Lawson, Matthew D Young, Yvette Hooks, Thomas R W Oliver, Timothy M Butler, James N Armitage, Tev Aho, Antony C P Riddick, Vincent Gnanapragasam, Sarah J Welsh, Kerstin B Meyer, Anne Y Warren, Maxine G B Tran, Grant D Stewart, Isidro Cortés-Ciriano, Sam Behjati, Menna R Clatworthy, Peter J Campbell, Sarah A Teichmann, Thomas J Mitchell

Faculty, Staff and Student Publications

Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8+ T cell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell …

Tilsotolimod Exploits The Tlr9 Pathway To Promote Antigen Presentation And Type 1 Ifn Signaling In Solid Tumors: A Multicenter International Phase I/Ii Trial (Illuminate-101), Hani Babiker, Erkut Borazanci, Vivek Subbiah, Sanjiv Agarwala, Alain Algazi, Jacob Schachter, Michael Lotem, Corinne Maurice-Dror, Daniel Hendler, Shah Rahimian, Hans Minderman, Cara Haymaker, Daruka Mahadevan, Chantale Bernatchez, Ravi Murthy, Rolf Hultsch, Nadia Kaplan, Gregory Woodhead, Charles Hennemeyer, Srinivas Chunduru, Peter M Anderson, Adi Diab, Igor Puzanov

Faculty, Staff and Student Publications

PURPOSE: Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated antitumor activity in preclinical models. The ILLUMINATE-101 phase I study explored the safety, dose, efficacy, and immune effects of intratumoral (it) tilsotolimod monotherapy in multiple solid tumors.

PATIENTS AND METHODS: Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the …

Neoadjuvant Chemotherapy Is Associated With Altered Immune Cell Infiltration And An Anti-Tumorigenic Microenvironment In Resected Pancreatic Cancer, Andressa Dias Costa, Sara A Väyrynen, Akhil Chawla, Jinming Zhang, Juha P Väyrynen, Mai Chan Lau, Hannah L Williams, Chen Yuan, Vicente Morales-Oyarvide, Dalia Elganainy, Harshabad Singh, James M Cleary, Kimberly Perez, Kimmie Ng, William Freed-Pastor, Joseph D Mancias, Stephanie K Dougan, Jiping Wang, Douglas A Rubinson, Richard F Dunne, Margaret M Kozak, Lauren Brais, Emma Reilly, Thomas Clancy, David C Linehan, Daniel T Chang, Aram F Hezel, Albert C Koong, Andrew J Aguirre, Brian M Wolpin, Jonathan A Nowak

Faculty, Staff and Student Publications

PURPOSE: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood.

DESIGN: We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient …

Oxphos Promotes Apoptotic Resistance And Cellular Persistence In Th17 Cells In The Periphery And Tumor Microenvironment, Hanna S Hong, Nneka E Mbah, Mengrou Shan, Kristen Loesel, Lin Lin, Peter Sajjakulnukit, Luis O Correa, Anthony Andren, Jason Lin, Atsushi Hayashi, Brian Magnuson, Judy Chen, Zhaoheng Li, Yuying Xie, Li Zhang, Daniel R Goldstein, Shannon A Carty, Yu Leo Lei, Anthony W Opipari, Rafael J Argüello, Ilona Kryczek, Nobuhiko Kamada, Weiping Zou, Luigi Franchi, Costas A Lyssiotis

Faculty, Staff and Student Publications

T cell proliferation and cytokine production are bioenergetically and biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, and attrition of the immune response. Interleukin-17-producing CD4 T cells (TH17s) are mediators of host defense, autoimmunity, and antitumor immunity in the setting of adoptive T cell therapy. TH17s are long-lived cells that require mitochondrial oxidative phosphorylation (OXPHOS) for effector function in vivo. Considering that TH17s polarized under standardized culture conditions are predominately glycolytic, little is known about how OXPHOS regulates TH17 processes, such as their ability to persist and thus contribute to …

Spatially Aware Dimension Reduction For Spatial Transcriptomics, Lulu Shang, Xiang Zhou

Faculty, Staff and Student Publications

Spatial transcriptomics are a collection of genomic technologies that have enabled transcriptomic profiling on tissues with spatial localization information. Analyzing spatial transcriptomic data is computationally challenging, as the data collected from various spatial transcriptomic technologies are often noisy and display substantial spatial correlation across tissue locations. Here, we develop a spatially-aware dimension reduction method, SpatialPCA, that can extract a low dimensional representation of the spatial transcriptomics data with biological signal and preserved spatial correlation structure, thus unlocking many existing computational tools previously developed in single-cell RNAseq studies for tailored analysis of spatial transcriptomics. We illustrate the benefits of SpatialPCA for …

Triple Blockade Of Ido-1, Pd-L1 And Mek As A Potential Therapeutic Strategy In Nsclc, Carminia Maria Della Corte, Vincenza Ciaramella, Kavya Ramkumar, Giovanni Vicidomini, Alfonso Fiorelli, Valerio Nardone, Salvatore Cappabianca, Immacolata Cozzolino, Federica Zito Marino, Gaetano Di Guida, Qi Wang, Robert Cardnell, Carl Michael Gay, Davide Ciardiello, Erika Martinelli, Teresa Troiani, Giulia Martini, Stefania Napolitano, Jing Wang, Lauren Averett Byers, Fortunato Ciardiello, Floriana Morgillo

Faculty, Staff and Student Publications

BACKGROUND: Despite the recent progress in the treatment and outcome of Non Small Cell Lung Cancer (NSCLC), immunotherapy has still significant limitations reporting a significant proportion of patients not benefiting from therapy, even in patients with high PD-L1 expression. We have previously demonstrated that the combined inhibition of MEK and PD-L1 in NSCLC patients derived three dimensional cultures exerted significant synergistic effect in terms of immune-dependent cancer cell death. However, subsequent experiments analyzing the expression of Indoleamine 2,3-dioxygenase-1 (Ido-1) gene expression demonstrated that Ido-1 resulted unaffected by the MEK inhibition and even increased after the combined inhibition of MEK and …

Chronic Exposure To Carbon Black Ultrafine Particles Reprograms Macrophage Metabolism And Accelerates Lung Cancer, Cheng-Yen Chang, Ran You, Dominique Armstrong, Ashwini Bandi, Yi-Ting Cheng, Philip M Burkhardt, Luis Becerra-Dominguez, Matthew C Madison, Hui-Ying Tung, Zhimin Zeng, Yifan Wu, Lizhen Song, Patricia E Phillips, Paul Porter, John M Knight, Nagireddy Putluri, Xiaoyi Yuan, Daniela C Marcano, Emily A Mchugh, James M Tour, Andre Catic, Laure Maneix, Bryan M Burt, Hyun-Sung Lee, David B Corry, Farrah Kheradmand

Faculty, Staff and Student Publications

Chronic exposure to airborne carbon black ultrafine (nCB) particles generated from incomplete combustion of organic matter drives IL-17A-dependent emphysema. However, whether and how they alter the immune responses to lung cancer remains unknown. Here, we show that exposure to nCB particles increased PD-L1+ PD-L2+ CD206+ antigen-presenting cells (APCs), exhausted T cells, and Treg cells. Lung macrophages that harbored nCB particles showed selective mitochondrial structure damage and decreased oxidative respiration. Lung macrophages sustained the HIF1α axis that increased glycolysis and lactate production, culminating in an immunosuppressive microenvironment in multiple mouse models of non-small cell lung cancers. Adoptive transfer of lung APCs …

Pancreatic Tumor Microenvironmental Acidosis And Hypoxia Transform Gold Nanorods Into Cell-Penetrant Particles For Potent Radiosensitization, Pradipta Ranjan Rauta, Yuri Mackeyev, Keith Sanders, Joseph B K Kim, Valeria V Gonzalez, Yasmin Zahra, Muhammad A Shohayeb, Belal Abousaida, Geraldine V Vijay, Okan Tezcan, Paul Derry, Anton V Liopo, Eugene R Zubarev, Rickey Carter, Pankaj Singh, Sunil Krishnan

Faculty, Staff and Student Publications

Coating nanoparticles with stealth epilayers increases circulation time by evading opsonization, macrophage phagocytosis, and reticuloendothelial sequestration. However, this also reduces internalization by cancer cells upon reaching the tumor. We designed gold nanorods (GNRs) with an epilayer that retains stealth properties in circulation but transforms spontaneously in the acidotic tumor microenvironment to a cell-penetrating particle. We used a customized stoichiometric ratio of l-glutamic acid and l-lysine within an amphiphilic polymer of poly(l-glutamic acid-co-l-lysine), or P(Glu-co-Lys), to effect this transformation in acidotic environments. P(Glu-co-Lys)-GNRs were internalized by cancer cells to facilitate potent in vitro radiosensitization. When administered intravenously in mice, they accumulate …

Blockade Of Fgf2/Fgfr2 Partially Overcomes Bone Marrow Mesenchymal Stromal Cells Mediated Progression Of T-Cell Acute Lymphoblastic Leukaemia, Chen Tian, Yueyang Li, Lina Wang, Junqi Si, Yaxin Zheng, Junnan Kang, Yafei Wang, M James You, Guoguang Zheng

Faculty, Staff and Student Publications

The development of acute lymphoblastic leuakemia (ALL) is partly attributed to the effects of bone marrow (BM) microenvironment, especially mesenchymal stromal cells (MSCs), which interact bilaterally with leukaemia cells, leading to ALL progression. In order to find MSCs-based microenvironment targeted therapeutic strategies, Notch1-induced T-cell ALL (T-ALL) mice models were used and dynamic alterations of BM-MSCs with increased cell viability during T-ALL development was observed. In T-ALL mice derived stroma-based condition, leukaemia cells showed significantly elevated growth capacity indicating that MSCs participated in leukaemic niche formation. RNA sequence results revealed that T-ALL derived MSCs secreted fibroblast growth factor 2 (FGF2), which …

Epacadostat Plus Pembrolizumab And Chemotherapy For Advanced Solid Tumors: Results From The Phase I/Ii Echo-207/Keynote-723 Study, John D Powderly, Samuel J Klempner, Aung Naing, Johanna Bendell, Ignacio Garrido-Laguna, Daniel V T Catenacci, Matthew H Taylor, James J Lee, Fred Zheng, Feng Zhou, Xiaohua Gong, Hema Gowda, Gregory L Beatty

Faculty, Staff and Student Publications

Background: Epacadostat, an oral, selective inhibitor of IDO1, has shown activity when administered with pembrolizumab. We evaluated the addition of chemotherapy to epacadostat and pembrolizumab in patients with advanced or metastatic solid tumors. One proposed mechanism of resistance to PD-1 checkpoint inhibition is through immunosuppression mediated by L-kynurenine. IDO1, indoleamine-2,3-dioxygenase 1 is the rate-limiting enzyme catalyzing the conversion of L-tryptophan to L-kynurenine. If IDO1 is a mechanism of tumor escape from checkpoint inhibition, then addition of an IDO1 inhibitor with a PD-1 checkpoint inhibitor could enable tumor response to immunotherapy.

Methods: Patients received one of 7 tumor-appropriate chemotherapy regimens. Pembrolizumab …

Tp53-Mutated Myelodysplastic Syndrome And Acute Myeloid Leukemia: Biology, Current Therapy, And Future Directions, Naval G Daver, Abhishek Maiti, Tapan M Kadia, Paresh Vyas, Ravindra Majeti, Andrew H Wei, Guillermo Garcia-Manero, Charles Craddock, David A Sallman, Hagop M Kantarjian

Faculty, Staff and Student Publications

UNLABELLED: TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct group of myeloid disorders with dismal outcomes. TP53-mutated MDS and AML have lower response rates to either induction chemotherapy, hypomethylating agent-based regimens, or venetoclax-based therapies compared with non-TP53-mutated counterparts and a poor median overall survival of 5 to 10 months. Recent advances have identified novel pathogenic mechanisms in TP53-mutated myeloid malignancies, which have the potential to improve treatment strategies in this distinct clinical subgroup. In this review, we discuss recent insights into the biology of TP53-mutated MDS/AML, current treatments, and emerging therapies, including immunotherapeutic and nonimmune-based approaches …

Melanoma Central Nervous System Metastases: An Update To Approaches, Challenges, And Opportunities, Alcida Karz, Maya Dimitrova, Kevin Kleffman, Christopher Alvarez-Breckenridge, Michael B Atkins, Adrienne Boire, Marcus Bosenberg, Priscilla Brastianos, Daniel P Cahill, Qing Chen, Sherise Ferguson, Peter Forsyth, Isabella C Glitza Oliva, Sarah B Goldberg, Sheri L Holmen, Jonathan P S Knisely, Glenn Merlino, Don X Nguyen, Michael E Pacold, Eva Perez-Guijarro, Keiran S M Smalley, Hussein A Tawbi, Patrick Y Wen, Michael A Davies, Harriet M Kluger, Janice M Mehnert, Eva Hernando

Faculty, Staff and Student Publications

Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy, and targeted therapy. Advances in the basic scientific understanding …

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 …

Potential Focal Adhesion Kinase Inhibitors In Management Of Cancer: Therapeutic Opportunities From Herbal Medicine, Feiyu Chen, Zhangfeng Zhong, Cheng Zhang, Yuanjun Lu, Yau-Tuen Chan, Ning Wang, Di Zhao, Yibin Feng

Faculty, Staff and Student Publications

Focal adhesion kinase (FAK) is a multifunctional protein involved in cellular communication, integrating and transducing extracellular signals from cell-surface membrane receptors. It plays a central role intracellularly and extracellularly within the tumor microenvironment. Perturbations in FAK signaling promote tumor occurrence and development, and studies have revealed its biological behavior in tumor cell proliferation, migration, and adhesion. Herein we provide an overview of the complex biology of the FAK family members and their context-dependent nature. Next, with a focus on cancer, we highlight the activities of FAK signaling in different types of cancer and how knowledge of them is being used …

Advances In Understanding Cancer-Associated Neurogenesis And Its Implications On The Neuroimmune Axis In Cancer, Ismail Yaman, Didem Ağaç Çobanoğlu, Tongxin Xie, Yi Ye, Moran Amit

Faculty, Staff and Student Publications

Nerves and immunologic mediators play pivotal roles in body homeostasis by interacting with each other through diverse mechanisms. The spread of nerves in the tumor microenvironment increases tumor cell proliferation and disease progression, and this correlates with poor patient outcomes. The effects of sympathetic and parasympathetic nerves on cancer regulation are being investigated. Recent findings demonstrate the possibility of developing therapeutic strategies that target the tumor microenvironment and its components such as immune cells, neurotransmitters, and extracellular vesicles. Therefore, examining and understanding the mechanisms and pathways associated with the sympathetic and parasympathetic nervous systems, neurotransmitters, cancer-derived mediators and their interactions …

Nab-Paclitaxel, Capecitabine, And Radiation Therapy After Induction Chemotherapy In Treating Patients With Locally Advanced And Borderline Resectable Pancreatic Cancer: Phase 1 Trial And Imaging-Based Biomarker Validation, Eugene J Koay, Mohamed Zaid, Maureen Aliru, Polycarpe Bagereka, Arie Van Wieren, Maria Jovie Rodriguez, Galia Jacobson, Robert A Wolff, Michael Overman, Gauri Varadhachary, Shubham Pant, Huamin Wang, Ching-Wei Tzeng, Naruhiko Ikoma, Michael Kim, Jeffrey E Lee, Matthew Hg Katz, Eric Tamm, Priya Bhosale, Cullen M Taniguchi, Emma B Holliday, Grace L Smith, Ethan B Ludmir, Bruce D Minsky, Christopher H Crane, Albert C Koong, Prajnan Das, Xuemei Wang, Milind Javle, Sunil Krishnan

Faculty, Staff and Student Publications

PURPOSE: Effective consolidative chemoradiation (CRT) regimens are lacking. In this phase 1 trial, we evaluated the safety and efficacy of nab-paclitaxel, capecitabine, and radiation therapy after induction chemotherapy in patients with locally advanced and borderline-resectable pancreatic cancer (LAPC and BRPC). Also, we evaluated a computed tomography (CT)-based biomarker of response.

METHODS AND MATERIALS: Eligible patients had pathologically confirmed pancreatic ductal adenocarcinoma, underwent computed tomography-imaging, received a diagnosis of LAPC or BRPC, and received induction chemotherapy. Standard 3 + 3 study design was used, with 3 escalating nab-paclitaxel dose levels (50, 75, and 100 mg/m

RESULTS: Twenty-three patients started and finished …

Differential Integrated Stress Response And Asparagine Production Drive Symbiosis And Therapy Resistance Of Pancreatic Adenocarcinoma Cells, Christopher J Halbrook, Galloway Thurston, Seth Boyer, Cecily Anaraki, Jennifer A Jiménez, Amy Mccarthy, Nina G Steele, Samuel A Kerk, Hanna S Hong, Lin Lin, Fiona V Law, Catherine Felton, Lorenzo Scipioni, Peter Sajjakulnukit, Anthony Andren, Alica K Beutel, Rima Singh, Barbara S Nelson, Fran Van Den Bergh, Abigail S Krall, Peter J Mullen, Li Zhang, Sandeep Batra, Jennifer P Morton, Ben Z Stanger, Heather R Christofk, Michelle A Digman, Daniel A Beard, Andrea Viale, Ji Zhang, Howard C Crawford, Marina Pasca Di Magliano, Claus Jorgensen, Costas A Lyssiotis

Faculty, Staff and Student Publications

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive …

Tumor Microenvironment: Barrier Or Opportunity Towards Effective Cancer Therapy, Aadhya Tiwari, Rakesh Trivedi, Shiaw-Yih Lin

Faculty, Staff and Student Publications

Tumor microenvironment (TME) is a specialized ecosystem of host components, designed by tumor cells for successful development and metastasis of tumor. With the advent of 3D culture and advanced bioinformatic methodologies, it is now possible to study TME's individual components and their interplay at higher resolution. Deeper understanding of the immune cell's diversity, stromal constituents, repertoire profiling, neoantigen prediction of TMEs has provided the opportunity to explore the spatial and temporal regulation of immune therapeutic interventions. The variation of TME composition among patients plays an important role in determining responders and non-responders towards cancer immunotherapy. Therefore, there could be a …

Single-Cell Transcriptomic Profiling Reveals The Tumor Heterogeneity Of Small-Cell Lung Cancer, Yanhua Tian, Qingqing Li, Zhenlin Yang, Shu Zhang, Jiachen Xu, Zhijie Wang, Hua Bai, Jianchun Duan, Bo Zheng, Wen Li, Yueli Cui, Xin Wang, Rui Wan, Kailun Fei, Jia Zhong, Shugeng Gao, Jie He, Carl M Gay, Jianjun Zhang, Jie Wang, Fuchou Tang

Faculty, Staff and Student Publications

Small-cell lung cancer (SCLC) is the most aggressive and lethal subtype of lung cancer, for which, better understandings of its biology are urgently needed. Single-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment (TME) and investigate their roles in tumorigenic processes. Here, we performed high-precision single-cell transcriptomic analysis of ~5000 individual cells from primary tumors (PTs) and matched normal adjacent tissues (NATs) from 11 SCLC patients, including one patient with both PT and relapsed tumor (RT). The comparison revealed an immunosuppressive landscape of human SCLC. Malignant cells in SCLC tumors exhibited diverse states mainly related …