tbuckley/cabot-search huggingface dataset:
Abstract PR014: DNA associated with EVs is uniquely chromatinized and prevents metastasis by enhancing anti-tumor immunity
Authors: Inbal Wortzel, Han-Sang Kim, David C. Lyden
Journal: Cancer Research (2024)

Abstract Cells release extracellular vesicles (EVs) loaded with functional biomolecules that facilitate intercellular communication in health and disease. These EVs contain DNA (EV-DNA), mirroring the mutational profile of parental cells, yet the mechanism of DNA packaging onto EVs and its role in diseases like cancer remain unclear. Using advanced imaging and biochemical techniques, we discovered that EV-DNA predominantly resides on the vesicle surface, bound to modified histones. Through genome-wide CRISPR knockout screens in cancer cell lines, we identified immune-related pathways and genes crucial for EV-DNA loading, such as APAF1 and NCF1. In several cancer models, loss of APAF1 reduced EV-DNA packaging, and enhancing metastasis, thus implicating EV-DNA in immune surveillance against cancer spread. We demonstrated that EV-DNA uptake by liver macrophages triggers DNA damage response, altering cytokine production and promoting immune activation in pre-metastatic sites. Moreover, quantifying EV-DNA in colorectal cancer biopsies revealed its potential as a predictive metastatic risk biomarker. Our findings shed light on EV-DNA packaging mechanisms and its significance, suggesting that elevated levels of tumor-derived EV-DNA bolster anti-tumor immunity and inhibit metastasis. Citation Format: Inbal Wortzel, Han-Sang Kim, David C. Lyden. DNA associated with EVs is uniquely chromatinized and prevents metastasis by enhancing anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR014.
Abstract IA009: Modulating amino acid cross talk between cancer and the host to improve diagnosis and therapy
Authors: Ayelet Erez
Journal: Cancer Research (2024)

Abstract Metabolic rewiring is a significant driver of cancer metastasis and presents a persistent challenge for therapy. Previously, we demonstrated that a high pyrimidine-to-purine ratio promotes tumor proliferation while enhancing the response to immunotherapy. Through a computational screen, we identified PDE5A as a target whose inhibition increases cGMP levels and, hence, could reduce GMP purine levels. We discovered that in addition to affecting the pyrimidine-to-purine ratio in cancers with high PDE5A expression, the PDE5A inhibitor Sildenafil (Viagra) induces the expression of cholesterol biosynthesis genes and metabolites across diverse cancer models. These metabolic shifts in cholesterol metabolism are associated with the accumulation of lipid droplets in the lysosomes and decreased cholesterol availability. Similarly, genetic inhibition of PDE5A using shPDE5A results in lysosomal cholesterol trafficking defects resembling Niemann-Pick disease type C (NPC1). Phenotypically, restricting PDE5A activity significantly inhibits cancer cell migration, invasion, proliferation, and colony formation. Moreover, Sildenafil restricts metastasis in mice and significantly increases survival rates in cancer patients compared to common antidepressants. Our findings position Sildenafil as a potent modulator of cholesterol metabolism in cancer, underscoring its potential use as an anti-cancer therapy. Furthermore, our results highlight the potential therapeutic opportunity in utilizing the host macroenvironment to indirectly rewire cancer metabolism. Citation Format: Ayelet Erez. Modulating amino acid cross talk between cancer and the host to improve diagnosis and therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA009.
Abstract C036: Pharmacological modulation of glutamine metabolism alters macrophage activity and tumor immune responses
Authors: Jiawei Fan, Sumeng Qi, Ie-Ming Shih, Tian-Li Wang
Journal: Cancer Research (2024)

Abstract As a critical component of innate and adaptive immunity, macrophages play an important role in shaping the tumor microenvironment (TME), which affects tumor initiation, progression, and response to treatment. Tumor-associated macrophages can display anti-tumor or pro-tumor activity, a cell fate attributed to macrophage polarization that depends on metabolomic regulation. Targeting macrophage metabolism could be a promising approach for cancer treatment by converting a pro-tumor TME into an anti-tumor TME. To examine in vivo mechanisms behind glutamine metabolism on macrophages, we treated immunocompetent murine ovarian cancer models with a clinical-grade glutamine prodrug, JHU083, and performed single-cell RNA sequencing (scRNAseq). In addition to the significant anti-tumor efficacy of JHU083, we found that JHU083 specifically suppressed the M2-like tumor macrophages while sparing M1-like macrophages. To better understand the molecular mechanism of how JHU083 causes macrophage polarization shift, we cultured an M1-like macrophage cell line with DON (6-Diazo-5-oxo-L-norleucine), the active component of JHU083, and performed bulk RNA sequencing. Using bulk RNAseq and scRNAseq transcriptome analyses on M1-like macrophages, glutamine inhibitor treatment significantly enhanced MHC class II genes, including CD74, H2-Aa, H2-Eb1, H2-Ea, H2-Ab1, and TNF family genes including Tnfsf12, and Tnfrsf14 which may promote T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironment. Moreover, DON-treated bone marrow-derived M1 macrophages promoted CD4+ T cell expansion. On the other hand, DON treatment significantly suppressed bone marrow-derived M2 macrophages. In conclusion, our findings suggest that glutamine metabolism reprogramming can promote anti-tumor functions in tumor macrophages. Therefore, targeting glutamine metabolism to regulate macrophage function and polarization can be a promising direction for future cancer therapy. Citation Format: Jiawei Fan, Sumeng Qi, Ie-Ming Shih, Tian-Li Wang. Pharmacological modulation of glutamine metabolism alters macrophage activity and tumor immune responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C036.
Abstract IA018: Determinants of B cell fate and function in cancer
Authors: Yuliya Pylayeva-Gupta
Journal: Cancer Research (2024)

Abstract Effector B cell responses in solid malignancies are associated with favorable response to immunotherapy. B cells can amplify anti-tumor immune responses via antibody production, antigen presentation, and pro-inflammatory cytokine release; yet B cells in cancer patients and tumor-bearing mice often fail to support these functions. We have evaluated the contribution of either systemic inflammatory cues or antigenic quality to B cell differentiation and function in cancer. First, we identify dysregulated transcriptional programs activated in pancreatic cancer-associated B cells that promote differentiation of naïve into immunosuppressive B cells and inhibit differentiation of anti-tumor plasma cells. Second, we find that systemic exposure to STING agonists potentiates expansion of immunosuppressive regulatory human and mouse IL35+ B lymphocytes. Finally, using a system where a B cell neoantigen is either soluble or tethered to the surface of cancer cells, we demonstrate that membrane-tethered antigen is sufficient to elicit activation of anti-tumor immunity and reduce tumor growth in a NK cell-dependent manner. Thus, inflammation and quality of antigen impact basic mechanisms governing B cell differentiation and the resulting immune response to solid malignancy with implications for vaccine engineering. Citation Format: Yuliya Pylayeva-Gupta. Determinants of B cell fate and function in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA018.
Abstract PR003: Sex-dependent changes in the aged melanoma tumor microenvironment influence metastasis and therapeutic responses
Authors: Yash Chhabra, Ashani T. Weeraratna
Journal: Cancer Research (2024)

Abstract There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear; while biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Dermal fibroblasts are known to have profound impact on melanoma progression. We examined if both sex-dependent and age-related changes in these fibroblasts can alter the course of melanoma tumor growth, visceral metastasis, and responses to therapy. We find that skin fibroblasts undergo age-mediated sex-differential changes in their proliferation, senescence, ROS production and stress response. We find that aged male fibroblasts drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging promotes sex- dimorphic BMP2 secretion exclusively by aged male fibroblasts, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. Our data provide an integrated view of how host factors such as advancing age and biological sex alter the tumor microenvironment and contribute to disease progression. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy and achieve gender-equitable healthcare. Citation Format: Yash Chhabra, Ashani T. Weeraratna. Sex-dependent changes in the aged melanoma tumor microenvironment influence metastasis and therapeutic responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR003.
Abstract PR018: Inflammation-induced mechanotransduction is necessary and sufficient to create pre-cancerous squamous lung metaplasias and necessary to drive progression to dysplasia
Authors: Thea D. Tisty, Deng Pan, Philippe Gascard, Joseph Caruso, Lorenzo Ferri, Chira Chen-Tanyolac
Journal: Cancer Research (2024)

Abstract Chronic exposure to tobacco smoke triggers chronic inflammation, fostering a fibrotic microenvironment and promoting the focal replacement of columnar human bronchial epithelial cells (hBECs) with cells exhibiting squamous morphology, termed metaplasia. How squamous metaplasia progresses to squamous dysplasia and, ultimately, squamous lung carcinoma is under intense investigation. Using human bronchial tissues, we demonstrate that, both in vitro and in vivo, cellular stress associated with chronic inflammation (e.g., oxidative stress, DNA damage) enhances TGF-β signaling and creates a fibroblast state exhibiting upregulated HSP47 expression, driving increased collagen fiber alignment, elevated tissue stiffness, and subsequent activation of YAP-dependent mechanotransduction in adjacent hBECs. These Stress/Tension-producing Instructive Fibroblasts (STIFs) alone were sufficient to induce hBECs to squamous metaplasia, precursors to tumor formation. Furthermore, when tumor suppressor function was compromised in hBECs, STIFs induced dysplastic phenotypes. Mechanistically, STIFs act in a dominant manner modulating epithelial cell identity and malignant phenotypes via extracellular matrix (ECM)-dependent mechanotransduction. Inhibition of HSP47-dependent collagen processing effectively prevented fibroblast-induced squamous metaplasia and dysplasia and was capable of reversing fibroblast-induced metaplasia, restoring bronchial epithelial cell identity. Citation Format: Thea D. Tisty, Deng Pan, Philippe Gascard, Joseph Caruso, Lorenzo Ferri, Chira Chen-Tanyolac. Inflammation-induced mechanotransduction is necessary and sufficient to create pre-cancerous squamous lung metaplasias and necessary to drive progression to dysplasia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR018.
Abstract C038: Harnessing NK cells to improve targeted therapy therapeutic efficacy in BRAF- mutant melanoma
Authors: Chia-Hsin Hsu, Andrew C. White
Journal: Cancer Research (2024)

Abstract Malignant melanoma is the most lethal form of skin cancer, with BRAFV600E as the most common driver mutation. Despite the success of BRAF/MEK inhibitors (BRAF/MEKi) as a standard-of-care, drug resistance occurs at high frequency and remains a concern to be overcome. In addition to suppressing cancer cell proliferation and survival, BRAF/MEKi treatment alters the tumor microenvironment to favor anti-tumor immunity, with extensive previous studies focusing on the T cell compartment. Investigating other immune components, such as natural killer (NK) cells, may offer new insights into improving the overall effectiveness of BRAF/MEKi. NK cells are innate immune cells that provide activating signals to cytotoxic T cells, in addition to their critical roles in tumor surveillance and metastasis. However, the role of NK cells as a component of the BRAF/MEKi response in melanoma remains largely unknown. To investigate the role of NK cells in BRAF/MEKi-mediated tumor control, we depleted NK cells in melanoma-bearing mice. We found that the tumors developed full resistance faster in the NK cell-depleted group than in controls. Moreover, quantification of tumor-infiltrating NK cells in different melanoma phases, including off-therapy growth, therapy-induced regression, drug- tolerant residual disease, and on-therapy regrowth and resistance, revealed a positive correlation between NK cell infiltration and the tumor response to BRAF/MEKi. We further increased NK cell infiltration during drug-tolerant residual disease by inhibiting Ptpn22, a potential negative regulator of activity in NK and other immune cell populations, resulting in a delayed onset of therapy resistance. These results demonstrate the indispensable role of NK cells in the BRAF/MEKi tumor response and their potential to improve the therapeutic efficacy of BRAF/MEKi. Citation Format: Chia-Hsin Hsu, Andrew C. White. Harnessing NK cells to improve targeted therapy therapeutic efficacy in BRAF- mutant melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C038.
Abstract PR006: Arginine dependent immuno-metabolic reprogramming by metabolic enzyme PFKFB4 underpins breast tumor immune tolerance
Authors: Tao Dai, Alphonse N. Dimeck, Hai Wang, Song Liu, Scott I. Abrams, Subhamoy Dasgupta
Journal: Cancer Research (2024)

Abstract Competition for nutrients in the tumor microenvironment (TME) can deprive cytotoxic T lymphocytes essential metabolites required for infiltration and activation. However, the underlying mechanisms by which tumor intrinsic oncogenic pathways control extracellular nutrient abundance to impart immunosuppressive TME is not well understood. Here, we show that oncogenic metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) constraints arginine availability in the TME, thereby suppressing CD8+ T cell cytotoxic functions allowing triple negative breast cancer (TNBC) immune evasion. Genetic ablation of PFKFB4 in breast tumor implantation mouse models resulted in tumor regression and effectively cleared residual tumors. Metabolic profiling of tumor interstitial fluid (TIF) demonstrated that increased arginine availability enhanced CD8+ T cell effector function in PFKFB4-depleted tumors. PFKFB4 is a bifunctional metabolic enzyme with a functional kinase and a phosphatase domain. Our mechanistic studies revealed that PFKFB4 functions as a protein kinase that phosphorylates and activates transcriptional coregulator NCOA3, which then induces NF-kB-dependent transcriptional activation of lipocalin-2, a siderophore-binding protein functioning as a cytokine. ELISA confirmed that increased secretion of lipocalin-2 by PFKFB4 reprogrammed the tumor-associated macrophages (TAMs) towards a pro-tumorigenic phenotype. This phenotypic switch triggered arginine catabolism, due to rapid induction of arginase 1 (ARG1)-positive macrophages, that metabolically out competed CD8+ T cells impeding their proliferation. Phenocycler-based immunostaining of human breast tissue microarray revealed that breast tumors with increased levels of PFKFB4 had reduced infiltrating CD8+ T cells associated with poor clinical outcome, underscoring our findings that immuno- metabolic crosstalk regulated by PFKFB4 is a critical mediator of immune evasion in TNBC. Citation Format: Tao Dai, Alphonse N. Dimeck, Hai Wang, Song Liu, Scott I. Abrams, Subhamoy Dasgupta. Arginine dependent immuno-metabolic reprogramming by metabolic enzyme PFKFB4 underpins breast tumor immune tolerance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR006.
Abstract PR005: Adiponectin inhibits high-fat diet feeding-induced tumor growth through restoration of anti-tumor activity of exhausted-CD8+ T cells
Authors: Kem Thi Nguyen, Hoon Pil Park
Journal: Cancer Research (2024)

Abstract There is a growing appreciation that obesity is one of the significant risk factors for the development of various types of cancers. Obesity has been shown to dysregulate the immune system, including alteration of immune population in tumor microenvironments (TME) and dysfunction of immune cells. Recent studies have also indicated that obesity induces dysregulation of hormones and cytokines production by adipose tissue, collectively called adipokines. Among them, downregulation of adiponectin is implicated in various types of diseases related to obesity. In this study, we examined the effect of adiporon, an adiponectin receptor agonist, on high-fat diet (HFD) feeding-induced breast tumor growth, and population and function of immune cells in the tumor microenvironment (TME) of obese mice. Adiporon significantly inhibits HFD-acceleration of breast tumor growth and restores the dysregulation of immune population in TME. In following experiments to elucidate the underlying mechanisms, we also found that treatment with adiporon protects CD8+ T lymphocyte from apoptosis induced by treatment with cancer cell culture media (CM) and palmitic acid (PA), while reducing various features of exhausted T cell, such as downregulation of PD-1 and Tim-3 expression and restoration of cytokine-production in CD8+ T cell. Treatment with globular adiponectin generates essentially similar effects, collectively indicating the positive effects of adiponectin on survival and function of exhausted CD8+ T cells. In addition, we found that stimulation with adiporon increased mitochondrial biogenesis and modulates mitophagy in CD8 + T cell exposed to CM and PA. In summary, adiponectin signaling restores the survival and anti-tumor activity of exhausted CD8+ T cells through modulation of mitochondrial homeostasis. Citation Format: Kem Thi Nguyen, Hoon Pil Park. Adiponectin inhibits high-fat diet feeding-induced tumor growth through restoration of anti-tumor activity of exhausted-CD8+ T cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR005.
Abstract C046: PARP inhibitors as immune modulators in metastatic ovarian cancer treatment
Authors: Sarka Vosahlikova, Peter Holicek, Irena Moserova, Michal Hensler, Romana Mikyskova, Lenka Kasikova, Josef Pasuvka, Jana Drozenova, Katerina Mojzisova, Marek Kovar, Iain McNiesh, Michael Halaska, Lukas Rob, Sandra Orsulic, Milan Reinis, Lorenzo Galluzzi, Radek Spisek, Jitka Palich Fucikova
Journal: Cancer Research (2024)

Abstract Epithelial ovarian carcinoma (EOC) is one of the top five causes of cancer-related death in women. Most patients with EOC achieve initial remission after primary or interval cytoreductive surgery combined with platinum-taxane chemotherapy. However, mutations in BRCA1 or BRCA2 genes, which lead to homologous recombination (HR) defects, play a crucial role in platinum sensitivity and justify the use of poly (ADP-ribose) polymerase (PARP) inhibitors as maintenance therapy, commonly linked to extended progression-free survival (PFS). Besides their direct cytotoxic and cytostatic effects, PARP inhibitors (PARPi) have shown significant immunostimulatory properties by disrupting DNA repair in cancer cells, and opening possibilities for synergy with immune checkpoint inhibitors (ICIs). In this study, we investigate the immunomodulatory effects of PARPi using multiparametric flow cytometry, multiplexed immunolabeling, single-cell transcriptomics, and functional assays in an experimental BR5Brca1-/- syngeneic mouse model and human EOC tumor samples. We examine the molecular and cellular mechanisms that can be exploited to develop more effective combination therapies. PARPi may increase the mutational burden in EOCs due to unresolved DNA damage and the release of damage-associated molecular patterns (DAMPs), thereby increasing T-cell infiltration. In addition, PARPi appear to promote potent type I interferon (IFN) secretion through the activation of cGAMP synthase and the stimulator of the interferon genes (STING) pathway. In combination with ICIs, PARPi showed a beneficial effect on the balance between adaptive anti-tumor immunity and innate myeloid components, leading to an improved cytotoxic T-cell response, as observed in mouse models and HGSOC tumor samples. These observations emphasize the role of strategically designed combinations of PARPi and immunotherapeutic agents, which could be the key to overcoming immunosuppression in the EOC microenvironment, thereby improving clinical outcomes. Citation Format: Sarka Vosahlikova, Peter Holicek, Irena Moserova, Michal Hensler, Romana Mikyskova, Lenka Kasikova, Josef Pasuvka, Jana Drozenova, Katerina Mojzisova, Marek Kovar, Iain McNiesh, Michael Halaska, Lukas Rob, Sandra Orsulic, Milan Reinis, Lorenzo Galluzzi, Radek Spisek, Jitka Palich Fucikova. PARP inhibitors as immune modulators in metastatic ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C046.