bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA16: Immune suppression in cancer and strategies for its reversal
Authors: Kaplan Rosandra N. 
Published: January 2022

Abstract
The microenvironment is involved in multiple aspect of cancer progression. Tumor metastasis is a critical step in the progression of solid tumors that is associated with patient mortality, and the metastatic microenvironment is key regulator of this process. The pre-metastatic niche is the microenvironment important for metastatic initiation that is established at distant sites in response to primary tumor factors during cancer progression. We characterized this microenvironment which involves changes in both stromal and immune populations in the lungs of sarcoma-bearing mice and in the liver in pancreatic- bearing mice by flow cytometry and RNA sequencing approaches. We identified a gene signature in pre-metastatic niche formation that demonstrates upregulation of immune suppression genes that is consistent across different metastatic tissue including lung and liver as well as across species with commonalities in murine and human early metastatic microenvironments. Performing single cell RNA sequencing of the pre-metastatic niche revealed key immune suppressive genes were found in the myeloid cell clusters. In addition to the increase of myeloid cells and immunosuppressive pathways, we discovered that T cell populations are reduced in pre-metastatic lungs. We hypothesized that reversing this immunosuppressive environment would restore T cell function and antitumor immunity. We designed a novel approach in which we generated Genetically-Engineered Myeloid cells (GEMys) to deliver IL-12, a potent antitumor molecule, into the pre-metastatic microenvironment. We evaluated the lungs by flow cytometry and observed that IL12-GEMy-treated mice had increased numbers of T cells and enhanced expression of activation markers, resulting in reduced metastasis and increased survival. This model was effective in an aggressive experimental metastasis model of pancreatic liver metastasis and was not only able to limit metastatic progression but was able to cure a subset of mice compared to rapid metastatic progression in the liver within a month in the untreated pancreatic cancer mice. When combined with chemotherapy pre-conditioning, IL12-GEMys cured mice of established tumors and generated long-lived T cell memory, as these mice were immune to subsequent tumor challenge. These studies demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.
Citation Format: Rosandra N. Kaplan. Immune suppression in cancer and strategies for its reversal [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA16.
Abstract IA17: The power of ONE: Immunology in the age of single cell genomics
Authors: Amit Ido 
Published: January 2022

Abstract
The immune system is a complex, dynamic and plastic network composed of various interacting cell types that are constantly sensing and responding to environmental cues. From very early on, the immunology field has invested great efforts to characterize the various immune cell types and elucidate their functions. However, accumulating evidence indicates that current technologies and classification schemes are limited in their ability to account for the functional heterogeneity of immune processes. Single cell genomics hold the potential to revolutionize the way we characterize complex immune cell assemblies and study their spatial organization, dynamics, clonal distribution, pathways, and crosstalk. This emerging field can greatly affect basic and translational research of the immune system. I will discuss how recent single cell genomic studies are changing our perspective of various immune related pathologies from cancer to autoimmune disease and neurodegeneration. Finally, I will consider recent and forthcoming technological and analytical advances in single cell genomics and their huge potential impact on the future of immunology research and immunotherapy.
Citation Format: Ido Amit. The power of ONE: Immunology in the age of single cell genomics [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA17.
Abstract IA18: Cancer metabolism: Emerging insights from single cell analysis
Authors: Locasale Jason W. 
Published: January 2022

Abstract
This presentation will focus on cancer metabolism and new insights that can be gained from emerging technologies – notably single cell analysis. I will first provide a brief overview of our laboratory's research program around metabolism, emphasizing the research questions we focus on as well as the technologies we've been developing and implementing. I will next discuss work on the development of computational tools using single cell expression data to investigate metabolic networks and pathway activity in single cells to study metabolism in vivo. I will show how this technology can be used to gain insights into metabolism within the tumor microenvironment in human tumors. I will next present an application of this technology in the study a therapeutic our lab has been studying, digoxin – a cardiac glycoside that is under consideration for repurposing in cancer and which we show to target glucose and central carbon metabolism. As a proof of concept, we demonstrate that remodeling of the immune compartment can be achieved upon introduction of this metabolic agent.
References: Sydney M. Sanderson, Zhengtao Xiao, Amy J. Wisdom, Shree Bose, Maria V. Liberti, Michael A. Reid, EmilyHocke, Simon G. Gregory, David G. Kirsch, Jason W. Locasale The Na+/K+ ATPase Regulates Glycolysis and Modifies Immune Metabolism in TumorsbioRxiv 2020.03.31.018739; doi: https://doi.org/10.1101/2020.03.31.018739 Xiao Z, Dai Z, Locasale JW. Metabolic landscape of the tumor microenvironment at single cell resolution. Nature Communications. 2019;10(1):3763. Epub 2019/08/23. doi: 10.1038/s41467-019-11738-0. PubMed PMID: 31434891; PMCID: PMC6704063.
Citation Format: Jason W. Locasale. Cancer metabolism: Emerging insights from single cell analysis [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA18.
Abstract IA21: Understanding responses to cancer therapy: The tissue is the issue, the scoop is in the poop, and you are what you eat
Authors: Wargo Jennifer A. 
Published: January 2022

Abstract
We have made major advances in cancer treatment using multi-modality therapy, with immunotherapy now playing a major role across cancer types. However, responses to treatment are not universal, and strategies to improve outcomes (and to ultimately prevent cancer altogether) are needed. Tissue-based analyses in neoadjuvant and other studies have yielded important insights into known and novel therapeutic targets, leading to rational combination strategies to improve outcomes to therapy. Additionally, next-generation sequencing approaches have allowed interrogation of the microbiome in the tumor, and also in the gut and other niches. Microbiota within the body have a profound impact on physiology, with emerging evidence that they may contribute to carcinogenesis and therapy response. Importantly, it is not only the microbes that matter, but also the substrate for energy use (i.e. our diet). All of these aspects will be discussed in this talk, and rational combination strategies to improve cancer treatment will be proposed.
Citation Format: Jennifer A. Wargo. Understanding responses to cancer therapy: The tissue is the issue, the scoop is in the poop, and you are what you eat [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA21.
Abstract P013: Germinal center hypoxia in tumor-draining lymph nodes negatively regulates humoral immune responses and affects the activation of tumor-infiltrating T cells
Authors: Firmino Natalie , Bennewith Kevin 
Published: January 2022

Abstract
Efforts to understand intrinsic and acquired resistance to anti-tumor immunotherapies have largely focused on characterizing factors within the primary tumor. However, lymph nodes are specialized hubs of immune response development, and an improved understanding of the microenvironmental conditions impacting immune cell activation in tumor-draining lymph nodes (TDLNs) may yield novel approaches for enhancing responses to anti-tumor immunotherapies. Using mouse models of breast cancer, we identified hypoxic regions amongst the B cell germinal center reactions of TDLNs. Injection of lethally irradiated tumor cells was sufficient to induce GC hypoxia, and hypoxia in TDLNs associated with the frequency of antibody- secreting cells. In vitro, hypoxia impaired the proliferation of activated B cells, and inhibited class-switching to IgG1 and IgA immunoglobulin isotypes. To assess the role of the hypoxic response in tumor-reactive GCs in vivo, we deleted von Hippel- Lindau factor (VHL) in class-switched B cells and found decreased GC B cells in TDLNs, and reduced class-switched and tumor-specific antibodies in the circulation, indicating that the hypoxic response negatively-regulates tumor-induced humoral immune responses. pVHL deletion in class-switched B cells also reduced the expression of activation markers amongst tumor-infiltrating T cells and increased the presence of M2-like macrophages within the primary tumor. We detected the hypoxia marker carbonic anhydrase IX in the GCs of LNs from breast cancer patients, providing the first line of evidence that hypoxia develops within human GCs and validating our observations of hypoxia in TDLNs of pre-clinical mammary tumor models. We conclude that GC hypoxia develops in TDLNs, and that the hypoxic response negatively regulates tumor-induced humoral immune responses in pre-clinical models, with consequent impacts on the phenotype tumor-infiltrating T cells and macrophages.
Citation Format: Natalie Firmino, Kevin Bennewith. Germinal center hypoxia in tumor-draining lymph nodes negatively regulates humoral immune responses and affects the activation of tumor-infiltrating T cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P013.
Abstract P018: Gut microbiota-driven alterations in tumor immunity can modulate the growth of metastatic brain tumors
Authors: Morad Golnaz , Johnson Sarah B. , Wargo Jennifer A. 
Published: January 2022

Abstract
Background: Metastatic brain tumors are associated with significant morbidity and mortality. The current limited understanding of the mechanisms underlying brain metastasis has hindered the development of efficient diagnostics and therapeutics for this disease. Microbiota has emerged as a novel hallmark of cancer, with a prominent role in tumorigenesis, tumor immunity, and response to treatment. However, the role of the microbiota in tumor metastasis, and in particular brain metastasis, is poorly understood. We hypothesize that distinct microbial communities can alter the immune microenvironment in the brain and modulate the different steps of brain metastasis formation.
Methods: To explore the role of gut microbiota in brain metastasis, we depleted gut microbiota in conventionally raised mice using a broad-spectrum non-absorbable antibiotic regimen. Subsequently, melanoma tumor cells were injected intracranially to evaluate the effect of gut microbiota depletion and associated immune changes on tumor growth. Tumor growth was measured through in vivo bioluminescent imaging and histology. Peripheral and tumor immune profiling was conducted through flow cytometry and immunohistochemistry.
Results: Depletion of the gut microbiota in mice decreased tumor growth in the brain. Evaluation of the peripheral and tumor immune profiles suggested the underlying mechanisms to involve alterations in the circulating cytokine profiles and an increase in anti-tumor T cell activity.
Conclusion: Our clinical studies suggest the association of distinct microbial communities with brain metastasis. Our pre-clinical findings demonstrate that the absence of gut microbiota can modulate the regulation of T cell activity to induce an anti-tumor response in the brain. Further studies, currently in progress, will determine the mechanistic role of dysbiotic microbiota and distinct microbial communities in this process.
Citation Format: Golnaz Morad, Sarah B. Johnson, Jennifer A. Wargo. Gut microbiota-driven alterations in tumor immunity can modulate the growth of metastatic brain tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P018.
Abstract P019: Intra-tumoral nerves regulate the local immune response at the tumor bed
Authors: Restaino Anthony C. , Lucido Christopher T. , Barr Jeffrey , Vermeer Paola D. 
Published: January 2022

Abstract
Patients with highly innervated tumors have a worse prognosis than those with less innervated disease. However, the process by which intra-tumoral nerves contribute to poor outcomes remains unclear. Previously, we identified that head and neck squamous cell carcinomas (HNSCCs) are infiltrated by sensory (TRPV1+) nerves. To map the source of these tumor infiltrating nerves, we intra-tumorally injected the fluorescently tagged nerve tracer lectin, wheat germ agglutinin (WGA), in our hind limb placed HNSCC tumors. Similar to other nerve tracers, WGA is taken up at nerve terminals and retrogradely transported to the neural somas. WGA labeled the somas of dorsal root ganglia (DRG), identifying them as the source of intra-tumoral nerves. Traced nerves were further characterized by immunostaining and identified as TRPV1+ (sensory), consistent with our initial findings. To test the contributions of tumor innervation to tumor growth and survival, wildtype and TRPV1-DTA (genetically deleted of TRPV1+ neurons) mice were implanted with a mouse model of human papillomavirus-induced (HPV+) HNSCC, mEERL cells. The absence of TRPV1 nerves results in slower tumor growth and improves survival. To mechanistically define how depletion of intra-tumoral nerves reduce tumor growth, we first collected tumors 25 days after injection in the hind limb and stained with a 12-color antibody panel. Stained tumors were then analyzed with flow cytometry to identify differences in the infiltrative immune cell populations between tumors grown in C57Bl/6 control mice and our TRPV1-DTA mouse model. Flow cytometry analysis indicated a decrease in the infiltrative myeloid derived suppressor cell (MDSC) population following ablation of TRPV1+ nerves. To understand how loss of TRPV1+ nerves mediate changes in the infiltrative immune cell population we conducted cytokine array analysis of condition media from cancer cells alone and in co-culture with DRG. Results indicate a shift in secreted cytokines following co-culture with DRG. These data indicate that intra-tumoral sensory nerves are recruited from loco-regional DRG to tumors injected in the hind limb. Our data also suggest that ablation of TRPV1+ nerves alter the intra-tumoral MDSC population and, in this way, potentially contributes to tumor growth. Finally, co-culture of mEERL cells with DRG in vitro results in changes in secreted cytokines, potentially explaining the change in the infiltrative immune cell populations. Together, these data indicate a potential role for sensory nerves to regulate the local immune response in developing tumors.
Citation Format: Anthony C. Restaino, Christopher T. Lucido, Jeffrey Barr, Paola D. Vermeer. Intra-tumoral nerves regulate the local immune response at the tumor bed [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P019.
Abstract P022: Reciprocal influence of immune response and tumor hypoxia during glioblastoma progression
Authors: Sattiraju Anirudh , Marallano Valerie , Chen Zhihong , Kang Sangjo , Brusco Concetta , Ramakrishnan Aarthi , Shen Li , Hambardzumyan Dolores , Friedel Roland H. , Zou Hongyan 
Published: January 2022

Abstract
Tumor hypoxia is linked to poor outcome for glioblastoma (GBM), a highly malignant brain cancer, but underlying mechanisms and instigators that initiate tumor hypoxia remain unclear. We tracked tumor hypoxia in GBM in mice using a sensitive fluorescent reporter. We revealed that tumor hypoxia functions as a critical link between immune cells and tumor cells that drives malignant potency and immunosuppression in GBM. Single-cell RNA sequencing analysis revealed that hypoxic GBM cells are quiescent, display a mesenchymal transition, are more represented in recurrent GBM and predict worse patient outcome. Interestingly, the in vivo GBM hypoxia gene signatures surprisingly showed an enrichment for immune pathways. We unveiled two potential mechanisms of hypoxia-induced immunosuppression: by sequestrating activated immune cells in hypoxia zones, thus limiting inflammatory spread and cutting off immune cell communication, and by reprograming entrapped immune cells towards an immunotolerant state. Reciprocally, entrapped TAMs release CCL8 and IL1β as hypoxic niche factors that not only reinforce immune cell retainment in hypoxic cores, but also shape the transcriptional response of hypoxic GBM cells. Contrary to the conventional viewpoint that hypoxia arises from rapid tumor expansion outstripping vascular supply, we discovered anticancer immunity as an important driving force of tumor hypoxia; attenuating immune responses by implanting GBM in host mice with immunodeficiency or IL1β deletion greatly decreased GBM hypoxia. Altogether, our study revealed a reciprocal influence of anticancer immunity and tumor hypoxia, which has significant ramifications for prognosis and immunotherapy for GBM.
Citation Format: Anirudh Sattiraju, Valerie Marallano, Zhihong Chen, Sangjo Kang, Concetta Brusco, Aarthi Ramakrishnan, Li Shen, Dolores Hambardzumyan, Roland H. Friedel, Hongyan Zou. Reciprocal influence of immune response and tumor hypoxia during glioblastoma progression [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P022.
Abstract P024: Using innate immune ligands to activate adaptive immune cells for glioblastoma therapy
Authors: Baugh Richard T. , Khalique Hena , Lei-Rossmann Janet , Seymour Len 
Published: January 2022

Abstract
Glioblastoma (GBM) is one of the most aggressive and immunosuppressive brain tumors in adults. Despite conventional therapy of surgical resection, radiotherapy and temozolomide (TMZ) chemotherapy, tumors invariably recur and become resistant. The Natural Killer Group 2 Member D (NKG2D) receptor plays a key role in the innate immune control of cancers. The ligands for this receptor (NKG2DLs) are minimally expressed or absent on healthy cells. Stressed or malignant cells upregulate NKG2DLs, resulting in immune activation. We have developed a strategy targeting upregulated NKG2DLs on GBM cells with bi-specific T cell engagers (BiTEs). NKG2D BiTE contains a recombinant NKG2D receptor linked to an anti-CD3 domain. Simultaneous binding of the NKG2D BiTE to NKG2DLs on GBM cells and CD3 on T cells causes antigen-independent activation, pro-inflammatory cytokine release, and tumor cell death. Pre-treating GBM cells with radiation and TMZ causes further NKG2DL upregulation, increased NKG2D BiTE-mediated T cell activation, and sensitises GBM cells to T cell lysis. Meanwhile, healthy non-cancer cells exposed to the same pre-treatment do not trigger T cell activation with NKG2D BiTE. To deliver the BiTE directly into the tumor, the NKG2D BiTE has been encoded into the genome of an oncolytic herpes simplex virus 1 (oHSV-1). This oHSV is capable of selective infection, replication and cell lysis within GBM cells, but not healthy cells. Alongside the direct oncolytic capacity of the oHSV-1, it can also act as a gene therapy vector to express the NKG2D BiTE in situ to activate endogenous tumor infiltrating lymphocytes and direct cytotoxicity towards the remaining cancer cells. Combining conventional radio/chemotherapy with NKG2D BiTE immunotherapy presents an opportunity for synergy by enhancing NKG2DL expression on GBM cells and directing T cell lysis specifically towards these tumor cells, whilst avoiding responses towards non-cancerous cells. Meanwhile, local delivery of the NKG2D BiTE using an oncolytic virus endows tumor-specific expression directly within the tumor.
Citation Format: Richard T. Baugh, Hena Khalique, Janet Lei-Rossmann, Len Seymour. Using innate immune ligands to activate adaptive immune cells for glioblastoma therapy [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P024.
Abstract P029: Expression of galectin-3 and pro-inflammatory cytokines in gliomas: Implications and therapeutic potential
Authors: Caniglia John 
Published: January 2022

Abstract
Galectin-3 (gal-3) is an integral protein in gliomagenesis that has been implicated in a myriad of oncogenic processes such as metabolic adaptation, angiogenesis, and tumor invasiveness. Gal-3 also has a well characterized role as a harbinger of inflammation, inducing the release of pro-inflammatory cytokines including interleukin-1 beta (IL-1B) and interleukin 6 (IL-6). However, these findings have not been well translated to oncology to date. Data from The Cancer Genome Atlas (TCGA) shows that gal-3 is highly overexpressed in low grade gliomas as well as glioblastoma (n = 156) compared to healthy brain tissue (n = 5). Further analysis of data from the Chinese Glioma Genome Atlas shows high expression of gal-3, IL-1B, and Il-6 are each associated with significantly (p &lt; 0.001) worse survival in gliomas. Additionally, the expression of gal-3 is significantly correlated with both IL-1B and IL-6 expression across all malignant gliomas. In other cancers including neuroblastoma it has been shown that IL-6 expression is largely dependent upon gal-3 signaling pathways. This has been shown with regards to IL-1B as well, a molecule which along with IL-6 has been well described for promoting angiogenesis and metastasis. Given these cytokines' highly correlated expression to gal-3 in gliomas, it is likely that gal-3 is involved in inducing cytokine expression in glioma. Here we will discuss the myriad of signaling pathways through which gal-3 induces inflammatory cytokine release in cancer, the implications of these pathways on glioma progression, and the therapeutic potential of targeting this axis.
Citation Format: John Caniglia. Expression of galectin-3 and pro-inflammatory cytokines in gliomas: Implications and therapeutic potential [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P029.