bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B022: Targeting the innate immune checkpoint TREX1 elicits antitumor immunity through tumor-intrinsic cGAS-STING signaling
Authors: Xing Cong , Yan Nan 
Published: February 2025

Abstract
Three-prime repair exonuclease 1 (TREX1) is the major DNase in mammalian cells that degrades cytosolic DNA to prevent activation of the cGAS-STING pathway. Genotoxic stress, DNA damage, and radiotherapy induce TREX1 expression in cancer cells, allowing them to evade innate immune activation of type I interferon (IFN-I)-mediated antitumor response. How TREX1 can be targeted for cancer immunotherapy remains elusive. Here, we show that genetic deletion of TREX1 in tumors elicits robust antitumor immunity through tumor-intrinsic cGAS-STING activation, IFN-I signaling, and recruitment of CD8+ T cells. To therapeutically target TREX1, we perform a high-throughput small-molecule inhibitor screen of TREX1 using a cell-free DNase assay. We identify two lead compounds that inhibit TREX1 DNase activity at low micromolar concentrations, induce IFN-I signaling in cancer cells, and inhibit tumor growth in mice in a type I IFN receptor-dependent manner. Additionally, TREX1 inhibitor treatment sensitizes B16-F10 melanoma to anti-PD-1 immunotherapy. We further show that Trex1 knockout cancer cells elicit systemic antitumor immunity and can be used as autologous cancer vaccines to protect against future tumor challenge and metastasis. We also establish an inducible whole-body Trex1 knockout mouse model to simulate “on-demand” systemic TREX1 inactivation in adult mice. Sustained TREX1 loss in adult mice suppresses a broad range of solid tumors and metastatic tumors. Although TREX1 deficiency is associated with severe autoimmune diseases, inducible Trex1 knockout in adult mice does not cause immune toxicity, demonstrating feasibility of an immune-safe therapeutic window. Together, our data present multiple therapeutic modalities for targeting TREX1 using small-molecule inhibitors and as an autologous cancer vaccine, as well as antitumor efficacy and immune safety, which should pave the way for developing TREX1-targeted cancer immunotherapy.
Citation Format: Cong Xing, Nan Yan. Targeting the innate immune checkpoint TREX1 elicits antitumor immunity through tumor-intrinsic cGAS-STING signaling [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B022.
Abstract B023: Enhancing the efficacy of oncolytic virus immunotherapy using eicosapentaenoic acid in preclinical cancer models
Authors: Khumo Nametso Koobotse , Volpato Milene , Errington-Mais Fiona 
Published: February 2025

Abstract
Introduction Despite significant advances in cancer immunotherapy, response rates remain limited and variable across patients and cancer types. Oncolytic viruses (OVs) are cancer immunotherapeutic agents, which kill cancer cells and promote an anti-tumor immune response. However, upregulation of immune evasion pathways, such as COX-2 mediated prostaglandin E2 (PGE2) signaling by cells in the tumor microenvironment (TME), including tumor associated macrophages (TAMs), can hinder their immunotherapeutic potential. This study investigated whether combining OVs with eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid with anti-inflammatory properties, including inhibition of PGE2 production, could enhance OV anti-cancer activity. Methods Balb/c mice were injected with colorectal CT26 cells and treated with OV (reovirus), EPA, or a combination of both reovirus/EPA, and tumor growth was monitored. Upon sacrifice, immune cell infiltration within harvested tumors was assessed by immunohistochemistry (IHC). PGE2 and cytokine production was determined by ELISA while MTT assays were employed to measure cell growth inhibition, in vitro. Co-culture of cancer cells with human peripheral blood mononuclear cells (PBMCs) was used to generate tumor-associated macrophages (TAMs), which were then isolated by magnetic bead CD14+ cell separation Results Assessment of EPA and reovirus in vivo suggested that the combination treatment reduced tumor volume more than the single agent treatments and confirmed that EPA significantly reduced PGE2 production. The combination treatment strategy also significantly inhibited the production CXCL9 and reduced the percentage of arginase-1 positive cells, a marker of TAMs. In vitro, EPA supplementation did not alter abrogate reovirus direct oncolysis and furthermore potentially enhanced reovirus oncolysis of CT26 cells. Additionally, EPA supplementation hindered PGE2 production and significantly inhibited the in vitro generation of TAMs by 50-90%. Conclusion These results suggest that EPA could render the TME less immunosuppressive without compromising on the direct oncolytic effect of the virus, ultimately enhancing OV-based immunotherapy.
Citation Format: Nametso Koobotse Khumo, Milene Volpato, Fiona Errington-Mais. Enhancing the efficacy of oncolytic virus immunotherapy using eicosapentaenoic acid in preclinical cancer models [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B023.
Abstract B068: A novel murine model for interrogating immune response to tumor heterogeneity in non-small cell lung cancer
Authors: Oh Michael , Abascal Jensen W , Tran Linh M , Salehi-Rad Ramin , Lim Raymond J , Dumitras Camelia , Yean Cara , Xiao Sunny , Kahangi Bitta P , Crosson William P , Reyes Edgar Perez , Coleman Nalani , Rennels Austin K , Krysan Kostyantyn , Liu Bin , Dubinett Steven M 
Published: February 2025

Abstract
Resistance to immune checkpoint inhibitors (ICIs) represents a major barrier to effectively treating patients with NSCLC. Increased tumor heterogeneity has been linked with diminished response to ICIs, but the mechanisms underlying such an effect remain underexplored, in part due to the lack of models for studying the impact of heterogeneity. To address this issue, we have developed a novel murine model of NSCLC that utilizes clonal cell lines to modulate tumor heterogeneity. Specifically, we isolated single cells from a murine NSCLC cell line harboring 3 common driver mutations (Kras G12D Tp53 +/- Lkb1 -/- , or “KPL”). We mutagenized KPL cells with N-methyl-N-nitrosourea in order to increase the tumor mutational burden, and then isolated single cells to derive clonal cell lines. Whole exome sequencing and subsequent phylogenetic analysis of tumor mutations yielded categorization of these clones into 5 clusters. Clones within the same cluster demonstrated comparable in vivo growth kinetics and similar response to anti-PD-1 immunotherapy. These clones exhibited unique tumor immune microenvironments that did not fully correlate with genomic factors such as tumor mutation burden. Notably, heterogeneous polyclonal tumors grew more aggressively than monoclonal tumors, and they exhibited response to anti-PD-1 therapy that differed from the response seen in the component single clones. Tracking of individual clones with fluorescent proteins and mutation tracing illustrated clonal shifts induced by ICI treatment. Our results validate this system as a model of NSCLC that can modify tumor heterogeneity and provide insights into the effects of heterogeneity on ICIs and other immunotherapies.
Citation Format: Michael Oh, Jensen W Abascal, Linh M Tran, Ramin Salehi-Rad, Raymond J Lim, Camelia Dumitras, Cara Yean, Sunny Xiao, Bitta P Kahangi, William P Crosson, Edgar Perez Reyes, Nalani Coleman, Austin K Rennels, Kostyantyn Krysan, Bin Liu, Steven M Dubinett. A novel murine model for interrogating immune response to tumor heterogeneity in non-small cell lung cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B068.
Abstract B083: Centrosome De-clustering as an Immune-Modulating Radiosensitizer: Implications for Enhancing RT-Induced Innate Immunity
Authors: KIM JAE SUNG 
Published: February 2025

Abstract
Radiotherapy (RT) increases the number of centrosomes in cancer cells, leading to centrosome clustering that supports bipolar mitosis and tumor cell proliferation. Targeting centrosome clustering has emerged as a potential strategy to enhance RT effects in breast cancer cells. However, the role of centrosome de-clustering in activating innate immunity in response to RT is still unclear. Our study demonstrates that centrosome de-clustering in irradiated cancer cells influences the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-mediated immune response in monocytes and macrophages after co-culture. While centrosome de-clustering heightened mitotic errors and increased cytosolic dsDNA in breast cancer cells post-irradiation, it did not directly activate the cGAS-STING pathway in the cancer cells themselves. Notably, it triggered this pathway in human monocytes and mouse macrophages following co-culture with the irradiated cancer cells. These findings provide the first evidence that centrosome de-clustering in irradiated breast cancer cells promotes innate immune activation in tumor-associated immune cells, offering insights for potential immunotherapy strategies.
Citation Format: JAE SUNG KIM. Centrosome De-clustering as an Immune-Modulating Radiosensitizer: Implications for Enhancing RT-Induced Innate Immunity [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B083.
Abstract B086: Disease-critical macrophage populations interact with stroma to modulate the tumor microenvironment
Authors: Zhong Weiwei , Ansariola Mitra , Tatman Micaela , Wester Rachel , Van Naarden Braun Kim , Biswas Shameek 
Published: February 2025

Abstract
Myeloid cells in the tumor microenvironment (TME) exhibit diverse functions, from pro-tumor to anti-tumor. To elucidate myeloid heterogeneity, we developed a deep-learning model to annotate 20 myeloid subtypes in single-cell data. We identified two macrophage populations, macro_SPP1 and macro_C1QC, which were pan-cancer, enriched in tumors compared to normal tissues, and linked to clinical outcomes. Higher macro_SPP1 abundance correlated with IO non-responders, pre-IO treatment, and lower inflammation, while macro_C1QC showed the opposite trends. We developed and validated gene signatures to quantify these macrophages in bulk RNAseq. Applying these signatures to TCGA and real-world data, we confirmed that macro_SPP1 was associated with worse survival and poor IO response, whereas macro_C1QC was linked to better outcomes. Tumors with chromosome 9p21 deletions had higher macro_SPP1 and fibroblast signatures, suggesting a TME influence on macrophage heterogeneity. Cell-cell communication analysis in single-cell data revealed that fibroblasts sent the strongest signals to macrophages in lung and pancreatic cancers. Fibroblast-derived ligands such as FN1 and collagens exhibited stronger signaling to macro_SPP1 than macro_C1QC, and colocalized with macro_SPP1 spatially. Conversely, macro_SPP1 sent higher total signals to other cells in the TME than macro_C1QC, with SPP1 to fibroblasts and endothelial cells being the most differentiating signal. In summary, we identified two disease-critical macrophage populations: pro-tumor macro_SPP1 and anti-tumor macro_C1QC. We found interactions between macrophages and fibroblasts as key modulators of the TME.
Citation Format: Weiwei Zhong, Mitra Ansariola, Micaela Tatman, Rachel Wester, Kim Van Naarden Braun, Shameek Biswas. Disease-critical macrophage populations interact with stroma to modulate the tumor microenvironment [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B086.
Abstract B088: Axl regulation of NK cell activity creates an immunosuppressive tumor immune microenvironment in head and neck cancer
Authors: Harmon Regan L , Kostecki Kourtney L , Iida Mari , Harris Madelyn A , Crossman Bridget E , Bruce Justine , Salgia Ravi , Wheeler Deric L 
Published: February 2025

Abstract
Head and neck cancer (HNC), the sixth most common cancer worldwide, utilizes many strategies to evade the immune system, including manipulation of immune cell composition in the tumor immune microenvironment (TIME). Previous studies in our laboratory have demonstrated that the receptor tyrosine kinase Axl is a crucial driver of proliferation, survival, metastasis, and therapeutic resistance in HNC. This study explores the role of tumor-bound Axl in immune evasion in HNC. Using a series of Axl CRISPR knockout (AxlKO) cell lines (MOC2-398, MOC2-399, MOC2-400) from the immunologically "cold" MOC2 mouse model of HNC, we found that Axl loss significantly delayed tumor growth in immunocompetent C57BL/6 mice. Further, Axl loss led to a marked reduction of immunosuppressive cells- including MDSCs, Tregs, B cells, and neutrophils- accompanied by an enhanced infiltration of cytotoxic immune cells such as CD8+ T cells and NK cells within the TIME. To identify the immune cell population(s) responsible for the observed tumor growth delay, AxlKO tumors were implanted in immune-deficient mouse models, including NCG and athymic nude mice. While AxlKO tumor growth in athymic nude mice, which lack T-cells, was unchanged, tumor growth in NCG mice-which notably lack NK cells- was “rescued,” suggesting that NK cells may critically mediate the slowed growth of AxlKO tumors. These observations led us to hypothesize that Axl modulates NK cell recruitment and activation within the TIME. To test this, we first assessed in vitro NK cell cytotoxicity and found that Axl loss in tumor cells appeared to significantly enhance NK cell cytotoxicity. Further, NK cell depletion studies in C57BL/6 mice bearing AxlKO tumors demonstrated that the lack of NK cell "rescued" tumor growth in AxlKO models. To investigate if Axl regulates cytokines and chemokines relevant to NK cell recruitment and activation, we conducted analyses using NanoString nCounter, Luminex, and quantitative PCR. These revealed downregulation of NK modulators CD73 and CCL2, along with increased expression of CCL5 and CXCL10 in AxlKO tumor cells. These findings suggest that Axl regulates key immunomodulators to inhibit NK cell recruitment and activation, creating an immunosuppressive TIME that promotes HNC tumor growth.
Citation Format: Regan L Harmon, Kourtney L Kostecki, Mari Iida, Madelyn A Harris, Bridget E Crossman, Justine Bruce, Ravi Salgia, Deric L Wheeler. Axl regulation of NK cell activity creates an immunosuppressive tumor immune microenvironment in head and neck cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B088.
Abstract B100: Dietary Intervention in Melanoma Patients Treated with Immune Checkpoint Inhibitors
Authors: Shaverdashvili Khvaramze 
Published: February 2025

Abstract
The goal of the proposal is to determine how dietary intervention modulates gut microbiome and immune, proteomic, and metabolomic changes in immune checkpoint inhibitor (ICI)-treated melanoma patients. There is ample evidence that diet represents a major regulator of the gut microbiome. To uncover the mechanism used by specific diet interventions to modulate gut microbiome composition, immune, proteomic, and metabolomic changes we have designed the first prospective dietary intervention clinical trial with high-fermented food diet followed by high-fiber supplementation in melanoma patients treated with ICI. We hypothesize that dietary interventions with high-fermented food and high-fiber supplementation will promote intestinal microbial signatures that may enhance antitumor immunity through immune, proteomic, and metabolomic changes to potential clinical response and occurrence of immune-related adverse events (irAEs). The study aims are: 1) Longitudinally assess gut microbial signatures upon sequential high-fermented food and high-fiber supplementation in ICI-treated cancer patients. We hypothesize that diet modification will distinctly modulate gut microbial diversity and function. 2) To assess whether high-fermented food and high-fiber supplementation will exert distinct immunological, proteomic, and metabolomic effects in ICI-treated cancer patients. We will also assess the association between gut microbiome diversity and occurrence and frequency of irAEs. In summary, the proposed study will improve our understanding of how specific adjuvant dietary interventions can shape the human gut microbiome and modulate anti-tumor immunity in ICI-treated melanoma patients.
Citation Format: Khvaramze Shaverdashvili. Dietary Intervention in Melanoma Patients Treated with Immune Checkpoint Inhibitors [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B100.
Abstract B102: Clinical response to checkpoint inhibitors is associated with distinct gut bacteria that promote anti-tumor immunity through different mechanisms
Authors: Bakdash Ghaith , Popple Amy , Klisko Dominika , Hudson Robyne , Castan Laure , Villemin Clelia , Schreiber Fernanda , Berlato Chiara , Corrie Pippa , Sharpington Tim , Lawley Trevor D , Robinson Matthew J 
Published: February 2025

Abstract
The gut microbiome of cancer patients impacts response to immune checkpoint inhibitor (CPI) therapy. We have recently identified nine species of gut commensal bacteria that are all strongly associated with CPI response in four independent cohorts of advanced melanoma patients. A consortium of nine strains, each representing one of these species, synergistically inhibited tumor growth in combination with anti-PD1 in a syngeneic tumor model thereby demonstrating these bacteria as active drivers of the anti-tumor immune response. The mechanisms by which each of the nine bacteria exert their systemic anti-tumor effects was investigated using in vitro assays with primary human immune cells. Eight of the strains triggered dendritic cells maturation, which led to the induction of CD8+ Cytotoxic T Lymphocytes (CTLs) with very potent tumoricidal activity. In addition, metabolites derived from four of the bacterial species, from two different phyla, triggered CTLs to upregulate the expression of granzyme B (GzB) and Interferon (IFN)γ and kill tumor cells in vitro. Furthermore, the bacterial metabolites derived from a different species were able to counteract the CD8+ T cell inhibitory effects of in vitro generated tumor-associated macrophages (TAMs), restoring CTL cell proliferation and the expression of GzB and IFNγ. In summary, nine species of gut commensal bacteria were identified as being associated with CPI response in melanoma. All species directly activated dendritic cells to trigger potently tumoricidal CTLs. Certain bacteria promoted anti-tumor effects through metabolites that can either promote CTL activation or hinder the inhibitory effects of TAM within the tumor microenvironment. This demonstrates that different bacteria associated with CPI response can interact with the immune system in distinct ways to enhance the efficacy of CPIs. All nine strains have now been combined to create a Live Biotherapeutic Product, MB097. MELODY-1 (NCT06540391) is an ongoing phase 1b study to evaluate MB097 in combination with pembrolizumab in advanced melanoma patients.
Citation Format: Ghaith Bakdash, Amy Popple, Dominika Klisko, Robyne Hudson, Laure Castan, Clelia Villemin, Fernanda Schreiber, Chiara Berlato, Pippa Corrie, Tim Sharpington, Trevor D Lawley, Matthew J Robinson. Clinical response to checkpoint inhibitors is associated with distinct gut bacteria that promote anti-tumor immunity through different mechanisms [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B102.
Abstract B103: Attenuated Salmonella secreting interleukin-21 activates T-cells and induces anti-tumor effects
Authors: Han Minju , Kim Eunji , Jeong Minchan , Kim Solbi , Jeon Heung Jin , Lee Hyo Jin 
Published: February 2025

Abstract
The tumor microenvironment is often characterized by an immunosuppressive state, limiting the efficacy of immunotherapies. Although blocking programmed death-1 (PD-1) and its ligand (PD-L1) can activate the immune system, its clinical success is often limited, prompting the exploration of combination therapies. Recent research has renewed interest in using attenuated Salmonella strains as cancer therapeutics due to their ability to target tumors, stimulate immune responses, and promote tumor cell death, though complete tumor eradication remains a challenge. In this study, we aimed to enhance anti-tumor immunity by leveraging Salmonella-mediated delivery of interleukin-21 (IL-21) to activate the suppressed immune system within the tumor microenvironment. Using Salmonella’s flagellar type III secretion system, we engineered the strain to secrete IL-21 directly into the tumor. In a mouse model, we assessed the local immune response and tested the combination of Salmonella-mediated IL-21 delivery with anti-PD-L1 therapy. Our results confirmed IL-21 secretion and showed enhanced recruitment and activation of CD4+ and CD8+ T cells in the tumor. Mice receiving the combination treatment exhibited improved survival and reduced tumor growth compared to monotherapy. Safety studies confirmed the viability of the IL-21-secreting Salmonella strain for therapeutic use. This study highlights Salmonella as a promising platform for cancer immunotherapy.
Citation Format: Minju Han, Eunji Kim, Minchan Jeong, Solbi Kim, Heung Jin Jeon, Hyo Jin Lee. Attenuated Salmonella secreting interleukin-21 activates T-cells and induces anti-tumor effects [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B103.