tbuckley/cabot-search huggingface dataset:
Abstract 3919: Targeting tissue-resident macrophage progenitors by anti-IL34 restores anti-tumor immunity and suppresses tumor growth
Authors: Hui Chen, Jaroslav Zak, Mark Paradise, Guangfang Wang, John Teijaro, Mark Onaitis, Judith Varner
Journal: Cancer Research (2024)

Abstract Macrophages play important roles in tumor microenvironment, where they can promote immune suppression, tumor growth and resistance to checkpoint inhibitor therapy and are the focus of efforts to develop novel cancer therapeutics. Strategies to inhibit macrophage accumulation to suppress tumor growth by blocking their recruitment from circulation have been only partially effective, leading to the identification of roles in tumor progression for tissue resident macrophages that are seeded during embryonic development. We examined the origins of lung tumor associated macrophages using lineage tracing, flow cytometry, and single cell sequencing. By comparing gene expression profiles of resident F4/80hi Lyve1+ Ly6C- macrophages and Ly6C+ F4/80lo CCR2+ recruited macrophages in subcutaneous, lung, central nervous and renal normal and tumor tissues, we identified generic tissue resident macrophage and recruited macrophage transcriptomic signatures, revealing that resident macrophages are characterized by signatures of Myc driven proliferation, fatty acid and cholesterol metabolism and immune suppression, while recruited macrophages are characterized by signature of inflammation and immune stimulation. Resident macrophages were associated with worse outcomes in cancer patients than recruited macrophages. Single cell sequencing and flow cytometry of genetically engineered mouse models of CC10-Cre KrasG12D;p53-/- and SPC-Cre KrasG12D lung cancer revealed that lung tumor progression was characterized by extensive expansion of immune suppressive, Ki67+ resident alveolar macrophages and loss of T cells in the lung. Single cell transcriptomics identified IL-34 expressed exclusively by tumor cells as a possible driver of alveolar macrophage proliferation and IGF1 expressed by tumor associated alveolar macrophages as a possible regulator of tumor cell proliferation. Accordingly, blockade of IL-34 profoundly reduced tissue resident macrophage proliferation, stimulated recruitment of activated T cells, and suppressed growth of KrasG12D driven tumors. Analysis of TCGA data sets revealed that expression of IGF1 or IL34 was associated with reduced survival in lung, kidney, liver, head and neck and ovarian cancer. These studies identify key roles for IL-34 and IGF1 in solid tumor progression and suggest new therapeutic targets for the development of therapeutic strategies to stimulate anti-cancer immunity. Citation Format: Hui Chen, Jaroslav Zak, Mark Paradise, Guangfang Wang, John Teijaro, Mark Onaitis, Judith Varner. Targeting tissue-resident macrophage progenitors by anti-IL34 restores anti-tumor immunity and suppresses tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3919.
Abstract 3906: <i>Ex vivo</i> breast tumors for understanding the patient specific tumor microenvironment remodeling and drug responses
Authors: Elizabeth Martin, Megan Benz, Katie Hebert, Ethan Byrne, Frank Lau
Journal: Cancer Research (2024)

Abstract Breast cancer is a heterogeneous disease driven by cell-intrinsic and cell-extrinsic signaling cues. Many of these cues derive from the tumor microenvironment (TME), which is composed of adipocytes, vasculature, stem cells, immune cells, and the extracellular matrix (ECM). Through these diverse components, the TME modulates cellular proliferation, survival, and ultimately response to therapy. Despite this high-level understanding of tumor-TME crosstalk, no existing pre-clinical models accurately capture the TME in vitro. We overcame that hurdle by developing a method to maintain healthy human breast tissue (HBT) alive ex vivo for at least 8 weeks. By culturing breast cancer cells in that HBT, we created ex vivo breast tumors (EVBTs) that retained patient-specific features relevant to breast cancer including menopause status, obesity status, and response to therapy. Using these EVBTs, we demonstrate breast cancer subtype-specific alterations in lipid accumulation, ECM remodeling, and cytokine profiles. RNA sequencing showed that breast cancer cell line signatures were retained in the EVBTs system at 1 week and 2 weeks in vitro. We demonstrated donor-specific transcriptional changes to the core matrisome gene set. Finally, we demonstrate that our EVBTs retained patient-specific heterogeneity in response to standard of care endocrine therapy and neoadjuvant chemotherapies. Our novel tumor model allows for 1) real-time examination of breast cancer interactions with HBT and the TME and 2) the isolation of breast cancer-specific factors vs. patient-specific factors in the development and progression of breast cancer. Citation Format: Elizabeth Martin, Megan Benz, Katie Hebert, Ethan Byrne, Frank Lau. Ex vivo breast tumors for understanding the patient specific tumor microenvironment remodeling and drug responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3906.
Abstract 390: Direct interaction of Pin1 with HIF-prolyl hydroxylase 2: Implications for breast cancer cell growth and survival
Authors: Yanymee Nimesia Guillen Quispe, Su-Jung Kim, Soma Saeidi, Gyo-Jin Choi, Chaithanya Chelakkot, Tianchi Zhou, Sang-Beom Bang, Tae-Won Kim, Young-Kee Shin, Young-Joon Surh
Journal: Cancer Research (2024)

Abstract Prolyl hydroxylase domain 2 (PHD2) is the main hypoxia-inducible factor (HIF)-prolyl hydroxylase. PHD2 in normoxia hydroxylates specific proline residues in HIF-1α and HIF-2α, which facilitates their ubiquitination and proteasomal degradation. Although the activity of PHD2 is reduced in hypoxia, significant levels of residual activity of this monooxygenase are still detected under hypoxic conditions. However, its role under hypoxia is poorly understood. Peptidyl-prolyl isomerase (Pin1) binds to target proteins containing phosphorylated serine or threonine residues followed by proline (pS/T-P). As PHD2 harbors several pS/T-P motifs, it may be a potential substrate of Pin1. We found for the first time interaction between Pin1 and PHD2 in human breast cancer MDA-MB-231 cells in normoxic and hypoxic conditions. Additionally, the breast cancer tissue array showed elevated expression of PHD2 as well as Pin1 in tumors compared to adjacent normal tissues. LC-MS/MS spectrometry identified three amino acid residues (S125, T168, and S174) of PHD2 undergoing phosphorylation. Among these, serine 125 was found to be the principal site required for Pin1 binding. As a novel binding partner of Pin1, oncogenic PHD2 can be explored as a therapeutic target for the treatment of breast cancer. Citation Format: Yanymee Nimesia Guillen Quispe, Su-Jung Kim, Soma Saeidi, Gyo-Jin Choi, Chaithanya Chelakkot, Tianchi Zhou, Sang-Beom Bang, Tae-Won Kim, Young-Kee Shin, Young-Joon Surh. Direct interaction of Pin1 with HIF-prolyl hydroxylase 2: Implications for breast cancer cell growth and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 390.
Abstract 6124: A comprehensive pan-cancer study nominating NF-κB-mediated TNFA signaling-induced hypoxia as a risk factor in Hispanic cancer progression
Authors: Tagari Samanta, Jun Hyoung Park, Benny Abraham Kaipparettu
Journal: Cancer Research (2024)

Abstract The Hispanic (HA) population is the second largest racial/ethnic group in the United States after non-Hispanic White (NHW). Though the HA population usually has a lower reported incidence of cancers compared to NHW, there are racial disparities exist in the mortality rate of some of the cancers. Factors related to the Social Determinants of Health (SDOH), such as higher poverty rates, less education, and reduced access to health care, are known to increase the risk of diagnosing advanced-stage cancer in HA compared to the NHW population. The contribution of such SDOH in the HA cancer population has been studied in the past years. However, the contribution of biological and genetic mechanisms to HA cancer disparity has not been well understood. Thus, in this study, we performed a comprehensive analysis of different databanks to understand the common genetic and biological factors that contribute to the pan-cancer disparity in the HA population. To identify HA and NHW populations, we used self-reported racial/ethnic information. Analysis of the “All of Us” database suggested a high prevalence of infection-related cancers such as Liver, Stomach, and Cervix Uteri in the HA population compared to the NHW population. SEER database also showed an increased percentage of diagnoses with infection-related cancers and poor survival of the HA population with these cancers compared to the NHW. We then analyzed the TCGA transcriptome data from primary tumors from HA and NHW patients. We only selected cancers with data from at least ten patients in each group. TCGA data confirmed that the tumors from HA cancer patients primarily express high inflammatory and immune-responsive signatures. Specifically, we found a high enrichment of NF-κB induced TNFA signaling in HA tumors. We also observed a significant correlation between TNFA and Hypoxia signature in many HA cancers. Since hypoxia is known to be associated with resistance to radiation and chemotherapy, targeting the increased hypoxia signature in HA tumors may be critical for sensitizing HA patients to cancer therapy. Overall, our pan-cancer analyses suggest an increased prevalence of many infection-related cancers in the HA population. HA tumors are enriched with TNFA, NF-κB, and hypoxic signatures. Specific targeting of these signatures may be critical in managing the HA patients who currently suffer from racial disparity in cancer incidence and survival. Citation Format: Tagari Samanta, Jun Hyoung Park, Benny Abraham Kaipparettu. A comprehensive pan-cancer study nominating NF-κB-mediated TNFA signaling-induced hypoxia as a risk factor in Hispanic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6124.
Abstract 3930: The therapeutic implications of consensus genomic subtypes of gastric adenocarcinoma
Authors: Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Ju-Seog Lee
Journal: Cancer Research (2024)

Abstract Background: Gastric adenocarcinoma (GAC) is heterogeneous lethal disease in genomic and clinical level. Although the clinical relevance of genomic and molecular subtypes of GAC has been demonstrated, differences in classification methods have made it difficult to use these findings in clinical applications. We aim to examine a consensus of genomic subtypes and correlate them with clinical outcomes. Method: We collected genomic data from 2527 GAC tumors and divided the data into discovery (n = 1427) and validation sets (n = 1100). A cluster of clusters approach (COCA) was used to find consensus subtypes of gastric tumors. We constructed the GAC predictor of the integrated consensus subtype with 120 genes (GPICS120) and applied it to the validation data set in order to validate the clinical significance of the new subtypes. By analyzing genomic and proteomic data we evaluated each subtype's potential response rate to standard and experimental treatments such radiation therapy, targeted therapy, and immunotherapy and further validated their functional significance in cell line models. Results: We identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs) by integrating 8 previously established genomic subtypes. CGS1 is characterized by worst prognosis, remarkably high stem cell characteristics, high IGF1 expression, and low genomic alterations. CGS2 showed canonical epithelial gene expression patterns. CGS3 and CGS4 are characterized by high copy number alterations and low immune activity. CGS5 has highest mutation burden and moderately elevated immune activity that is characteristics of MSI-high tumors. The majority of CGS6 tumors have extremely high methylation, high immune activity, and are EBV-positive. The most intriguing finding is that CGS1 is the most responsive to immunotherapy whereas CGS3 is significantly associated with benefit of chemoradiation therapy due to high basal level of ferroptosis. Furthermore, we showed that ferroptosis inducer statin sensitized radiation-resistant GAC cells to ionizing radiation, suggesting that statin can be used to enhance the efficacy of chemoradiation in GAC and it would warrant further investigation in preclinical models. Conclusion: Consensus subtype is robust classification system and can serve as the basis for future clinical trials as well as pre-clinical research into targeted subtype-based therapies. Citation Format: Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Ju-Seog Lee. The therapeutic implications of consensus genomic subtypes of gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3930.
Abstract 7357: Comparative transcriptomic analysis reveals novel insights into targetable B-cell lymphoma mechanisms
Authors: Sehi Kim, Naomi Rapier-Sharman, Michael T. Told, Kim L. O’Neill, Brett E. Pickett
Journal: Cancer Research (2024)

Abstract B-cell lymphoma is a severe type of lymphatic cancer that is often misdiagnosed in adolescents. While some cases of B-cell lymphoma respond well to chemo- and radiation therapy, there are severe side effects, and many cases are refractory and fail to achieve remission. On the other hand, though CD19 CAR T-cell therapy is highly effective at treating B-cell lymphoma, its association with long-term immunocompromisation justifies the exploration of alternative treatments. Comparing B-cell lymphomas to an autoimmune disease that affects the same tissue type may grant us additional insights into immuno-oncology related treatments for B-cell lymphoma. We have developed a novel tool to compare cancer and autoimmune disease by analyzing bulk RNA-sequencing (RNA-seq) data. This algorithmic approach uses the transcriptional profile to improve our understanding of B-cell specific mechanisms that can be targeted in B-cell lymphoma. Using this tool, we compared the transcriptional signatures of primary B-cell lymphomas with primary B-cells from patients with systemic lupus erythematosus, an autoimmune disease. We identified specific genes and enriched functions associated with B-cell lymphoma’s immune signature. We expect that the results of our B-cell lymphoma analysis could be used to develop beneficial treatments alternative to current therapies, potentially mitigating side effects for B-cell lymphoma patients and increasing their quality of life. Citation Format: Sehi Kim, Naomi Rapier-Sharman, Michael T. Told, Kim L. O’Neill, Brett E. Pickett. Comparative transcriptomic analysis reveals novel insights into targetable B-cell lymphoma mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7357.
Abstract 392: MYB regulates a specific subset of hypoxia-induced genes and exhibits altered genomic occupancy under hypoxia
Authors: Shashi Anand, Mohammad Aslam Khan, Kunwar Somesh Vikramdeo, Seema Singh, Ajay Pratap Singh
Journal: Cancer Research (2024)

Abstract Hypoxia, an unavoidable microenvironmental stress, greatly influences the tumor cell behavior and therapeutic outcomes. Under low oxygen condition, tumor cells undergo transcriptional reprogramming, largely mediated through hypoxia-inducible factors (HIFs), triggering adaptive response pathways. We recently demonstrated a significant role of MYB in hypoxic survival of pancreatic cancer cells by facilitating adaptive changes in cellular metabolism in collaboration with HIF1α. Here, we employed genome-wide deep sequencing approaches to study the impact of hypoxia on transcriptional reprogramming of pancreatic cancer cells and investigate the role of MYB in the hypoxia-dependent processes. A large number of differentially expressed genes (DEGs) were identified in pancreatic cancer cells subjected to hypoxia (1% O2) and associated with multiple adaptive response pathways. Specifically, we found that pathways related to autophagy, cell migration, epithelial-to-mesenchymal transition, endocytosis, cytoskeleton reorganization were induced, while those associated with RNA processing, ribosome biogenesis, DNA replication and cell cycle were suppressed. To analyze the role of MYB in these adaptive responses, we compared the relative abundance of transcripts in MYB-overexpressing control and MYB knockout (KO) pancreatic cancer cells when cultured under normoxic or hypoxic conditions. We observed that the transcriptional output of MYB was drastically changed under hypoxia with a vast majority of genes being distinctly altered in response to the loss of MYB expression under normoxia and hypoxia. To examine if it resulted from altered genomic occupancy of MYB under normoxia and hypoxia, we compared MYB ChIP-seq peaks under these conditions. We observed a decrease in overall MYB-bound genomic regions under hypoxia despite the fact that we did not observe a decrease in nuclear MYB expression. More interestingly, the genomic occupancy of MYB shifted substantially from regions proximal to transcription start site to distal intergenic or intronic regions under hypoxia. Studies are currently underway to examine the mechanisms underlying the altered MYB genomic occupancy and its impact on adaptive physiological response of pancreatic cancer cells under hypoxia. Together, our findings bring unprecedented insight into the mechanistic role of MYB in hypoxia adaptation and pancreatic cancer pathobiology. Citation Format: Shashi Anand, Mohammad Aslam Khan, Kunwar Somesh Vikramdeo, Seema Singh, Ajay Pratap Singh. MYB regulates a specific subset of hypoxia-induced genes and exhibits altered genomic occupancy under hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 392.
Abstract 3921: The aged tumor microenvironment limits CD8+ T cell control of cancer
Authors: Alex C.Y. Chen, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Megan E. Fung, Sarah A. Weiss, Maria Zschummel, Kazuhiro Taguchi, Christopher S. Garris, Thorsten R. Mempel, Debattama R. Sen
Journal: Cancer Research (2024)

Abstract Aging is associated with progressive loss of immune function, which parallels the rise in cancer incidence. The etiology and impact of age-related CD8+ T cell dysfunction in cancer remain poorly understood. Here, we demonstrate that increased tumor growth in aged hosts is associated with reduced CD8+ T cell infiltration and function. The transfer of young antigen-specific CD8+ T cells fails to restore tumor control in aged hosts due to the rapid induction of CD8+ T cell dysfunction. The aged tumor microenvironment drives a novel age-associated dysfunctional state (TADys) that is functionally, transcriptionally, and epigenetically distinct from canonical CD8+ T cell exhaustion. Overall, this study focuses on understanding the cell-intrinsic and -extrinsic effects on CD8+ T cell immunity in aging and explores a proper strategy to improve CD8+ T cell control of cancer. Citation Format: Alex C.Y. Chen, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Megan E. Fung, Sarah A. Weiss, Maria Zschummel, Kazuhiro Taguchi, Christopher S. Garris, Thorsten R. Mempel, Debattama R. Sen. The aged tumor microenvironment limits CD8+ T cell control of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3921.
Abstract 1604: Cancer-associated fibroblasts modulate T cell killing activity &amp; phenotype in PDAC
Authors: Fouzia Zayou, Hayden Pearce, Samantha Nicol, Sandra Margielewska-Davies, Sarah Powell-Brett, Rachel Brown, Jianmin Zuo, Keith Roberts, Helen M. McGettrick, Paul Moss
Journal: Cancer Research (2024)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive malignancy characterised by its abundant extracellular matrix and diverse stromal cell components such as cancer associated fibroblasts (CAFs). CAFs play a pivotal role in shaping the tumour microenvironment and influencing the behaviour of immune cells, particularly T cells, through various mechanisms. The impact of CAFs on T cells is multifaceted as they can exert both pro- and anti-tumoral effects, influencing the delicate balance between immunosurveillance and immune evasion. In this study, we examined the phenotype and function of T cells when co-cultured with CAFs and Adjacent-normal fibroblasts (ANF) isolated from primary PDAC tissue following surgical resection. Methods: Tumour and juxta-tumoral tissue from patients underwent digestion into a single cell suspension. Subsequently, the isolated fibroblasts were cultured and stained with a 22-plex antibody panel designed for flow cytometry. Additional functional assays involved co-culture of CAFs and ANFs with unstimulated or anti-CD3/CD28 stimulated allogeneic T cells. Cell proliferation rates were quantified through the CFSE assay, while the T cells were simultaneously stained to distinguish CD4+ and CD8+ T cells subpopulations. Additionally, the expression of key co-stimulatory molecules: CD69, NKG2D and DNAM-1 and the co-inhibitory molecule: PD-1 were assessed, providing a thorough examination of the immune dynamics within the tumour microenvironment. Results: Flow Cytometry analysis revealed a distinct expression profile in CAFs compared to ANFs, with CAFs expressing higher levels of FAP and CD29. The CFSE assay further revealed that CAFs induced T cell proliferation of resting T cells with no significant increase in stimulated T cells. Notably, this co-culture led to a highly differentiated phenotype in both unstimulated and stimulated CD4+ and CD8+ T cells, characterised by elevated expression of activating markers (CD69 and NKG2D) and the inhibitory molecule PD-1. These findings suggest a dynamic interplay between fibroblasts and T cells in the tumour microenvironment, influencing both the proliferation and phenotypic aspects of T cell behaviour. Citation Format: Fouzia Zayou, Hayden Pearce, Samantha Nicol, Sandra Margielewska-Davies, Sarah Powell-Brett, Rachel Brown, Jianmin Zuo, Keith Roberts, Helen M. McGettrick, Paul Moss. Cancer-associated fibroblasts modulate T cell killing activity &amp; phenotype in PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1604.