tbuckley/cabot-search huggingface dataset:
Abstract 1590: The role of mucosal associated invariant T (MAIT) cells in pancreatic cancer liver metastasis
Authors: Jugmohit Toor, Peter Dimitrion, Rachel Krevh, Kalpana Subedi, Bobby Zuniga, Jie Wang, Li Zhou, Qing-Sheng Mi
Journal: Cancer Research (2024)

Abstract Pancreatic cancer liver metastasis (PCLM) is present in 50% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and leads to a median survival of &amp;lt;6 months. Here, we sought to identify urgently needed therapeutic options for treating PCLM by targeting mucosal associated invariant T (MAIT) cells, an invariant T cell restricted to MHCI related protein (MR1). MAIT cells are a unique subset of T cells that are classified as “protumor” MAIT17 and “antitumor” MAIT1 cells. We hypothesize that the PCLM tumor microenvironment (TME) induces direct MAIT cell activation via MR1 which primes MAIT cells towards a “protumor” phenotype. Using publicly available TCGA data, we found that PDAC tumors were enriched for MR1 gene expression compared to healthy tissue and patients with lower tumor MR1 expression had better overall survival. Next, immunostaining of MR1 on tumor samples from primary PDAC and PCLM revealed that that MR1 protein expression is highly enriched in the TME and localized to the surface of tumor cells. This suggests that MAIT cells in the PCLM TME are being activated directly via an MR1 dependent pathway. Next, we performed hemi-spleen injection of mouse pancreatic cancer cells into WT and MR1 KO (lacks MAIT cells) mice to model PCLM. Interestingly, MAIT cells in the WT PCLM mice were shifted towards the “pro-tumor” MAIT17 phenotype. Furthermore, the lack of MAIT cells in MR1 KO mice significantly reduced tumor burden compared to WT mice. Lastly, we found that MR1 KO mice had a reduction in exhausted NK and NKT cells which likely promoted anti-tumor immunity. Overall, we find that the PCLM TME promotes “pro-tumor” MAIT17 cells via MR1 mediated activation and these MAIT17 cells inhibit anti-tumor cells such as NK and NKT cells. This work identifies targeting MAIT cells as a novel immunotherapy approach for PCLM. Citation Format: Jugmohit Toor, Peter Dimitrion, Rachel Krevh, Kalpana Subedi, Bobby Zuniga, Jie Wang, Li Zhou, Qing-Sheng Mi. The role of mucosal associated invariant T (MAIT) cells in pancreatic cancer liver metastasis [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 1590.
Abstract 1060: Circulating early myeloid derived suppressor cells as biomarkers for early detection of lung cancer
Authors: Orazio Fortunato, Barbara Bassani, Mara Lecchi, Paolo Verderio, Ugo Pastorino, Gabriella Sozzi, Mario Paolo Colombo, Sabina Sangaletti
Journal: Cancer Research (2024)

Abstract Background. Lung cancer (LC) patients, despite innovative cancer treatments such as target and immune-therapies, still have the poorest five-year survival rate. In this context the possibility of an early detection can anticipate therapeutic intervention, avoiding aggressive therapies thus prolonging disease-free and overall survival. Therefore, the identification of new circulating early biomarkers still represents a relevant clinical need. Methods. Lung cancer (LC) patients (n=63) and heavy smokers (HS) cancer free-subjects (n=52) were evaluated for the enrichment of specific subtypes of myeloid cells. Circulating early myeloid derived suppressor cells (eMDSCs) and low-density neutrophils (LDNs) were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). Early MDSCs were defined as CD11b+CD33+CD15-CD14- cells among Lineage negative (Lin-) HLA-DR- PBMCs, whereas LDNs were defined as CD66b+CD15+ cells within the gate of CD11b+ PBMCs. Mature and immature subtypes were discriminated according to the expression of CD10. Results. Performing a sex- and smoking -matched case-control analysis in 39 LC and 39 HS subjects we were able to compare the capacity of specific myeloid population to discriminate lung cancer patients from heavy smokers. The analysis showed significantly higher values of eMDSC (OR=1.12; 95% Confidence Interval (CI) 1.03-1.21), total LDN (CD66b+CD15+; OR=1.23; 95%CI 1.04-1.45) and of mature CD10+ LDN (OR=1.30; 95%CI 1.05-1.61). Moreover, within the overall cohort of 63 LC patients, we analyzed the distributions of the different myeloid populations according to stage (I-II vs III-IV). In this comparison, total LDN (CD66b+CD15+; Kruskal-Wallis (KW) Test p-value=0.014), and mature CD10+ LDN (KW test p-value=0.006) showed significant different distributions according to tumor stage, observing higher values in patients with advanced stage. On the contrary, no difference among stages was observed for the eMDSC population. Conclusions. These findings point to eMDSCs as an early marker for lung cancer detection whereas LDN could be as well associated with disease progression. Citation Format: Orazio Fortunato, Barbara Bassani, Mara Lecchi, Paolo Verderio, Ugo Pastorino, Gabriella Sozzi, Mario Paolo Colombo, Sabina Sangaletti. Circulating early myeloid derived suppressor cells as biomarkers for early detection of lung 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 1060.
Abstract 1180: Asparagine deprivations enhance CD8+ T cell antitumor activity and ICB immunotherapy via ROS-mediated NFAT nuclear localization
Authors: Hsuan Chia Chang, Kwang-Huei Lin, Huang Yu Yang
Journal: Cancer Research (2024)

Abstract Metabolic reprogramming plays a crucial role in the differentiation and activation of T cells. Both oxidative phosphorylation (OXPHOS) and glycolysis are upregulated to meet the high energy demands. However, the impact of amino acid metabolism on T cell activation remains unclear. Our study demonstrates that asparagine deprivation enhances the antitumor activity of CD8+ cytotoxic T lymphocytes (CTLs) and increases the flux of glycolysis and the tricarboxylic acid (TCA) cycle. Mechanistically, asparagine deprivation induces the production of reactive oxygen species (ROS) through mitochondrial complex I deficiency and leads to nuclear localization of NFAT, subsequently affecting cytokine production and T cell activation. In the animal model, we found that the clinical drug leunase exhibits antitumor activity that relies on the immune response of T cells. Leunase treatment promotes the activation of tumor-infiltrating lymphocytes (TILs) in vivo. Furthermore, the combination therapy of leunase and anti-PD1 demonstrates a synergistic effect. In patients with nasopharyngeal carcinoma (NPC), leunase therapy enhances the cytokines production and activation of CD8+ T cell. In summary, our findings offer valuable insights into how T cells adapt to changes in their nutritional environment. Citation Format: Hsuan Chia Chang, Kwang-Huei Lin, Huang Yu Yang. Asparagine deprivations enhance CD8+ T cell antitumor activity and ICB immunotherapy via ROS-mediated NFAT nuclear localization [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 1180.
Abstract 1422: A novel gut microbiota therapeutic approach for enhancing immune checkpoint inhibitor therapy
Authors: Priscilla Del Valle, Gabriella Nguyen, Yongbin Choi, Parastoo Sabaeifard, Wenng li, Jake Lichterman, Laura Coughlin, Nicole Poulides, Angelica Sanjuan, Andrew Y. Koh
Journal: Cancer Research (2024)

Abstract Immune checkpoint inhibitor therapy (ICT) has revolutionized cancer care, but up to 50% of patients do not respond to ICT. A host factor implicated in variable ICT response is the gut microbiome: a) germfree/antibiotic-treated mice do not respond to ICT; b) human ICT responders have distinct gut microbiome signatures compared to non-responders; and c) fecal microbiota transplants are safe and potentially effective in cancer patients previously unresponsive to ICT. We have previously established that ICT induces translocation of gut microbiota into secondary lymphoid tissues (particularly the mesenteric lymph nodes) and tumor which is required to enhance extraintestinal anti-tumor immunity (PMID: 36867675). Here, we have developed a novel gut microbiota therapy (GMT) which circumvents the challenges and limitations of conventional microbiome therapies that use live microbes. GMT utilizes specific components derived from commensal gut microbiota identified in our published clinical study (PMID:28923537) that can be administered parenterally (subcutaneous/intravenous) to safely and reproducibly enhance ICT efficacy in multiple preclinical cancer models (B16-F10 with anti-PD-1 and/or CTLA-4, MC38 with or without anti-PD-1, humanized mouse with human melanoma and human anti-PD-1). GMT acts by agonizing the pattern recognition receptors hTLR1/2/6, hNOD2 and hSTING. GMT induces anti-tumor cytokines (IL-12) but does not significantly increase sepsis associated cytokines (IL-6, TNFa) in both human immune cells and in non-human primates. Mechanistically, GMT acts via dendritic cells, and potentially through increased expression of delta-like ligand protein 4 (DLL4), a Notch signaling ligand that activates Notch 1/4 in T cells and promotes Th1 and Th17 differentiation. Current efforts to identify the active components of GMT are underway in which we have used serial liquid-liquid extractions (ethyl acetate followed by water:methanol:chloroform) and subsequent reverse phase chromatography to identify the most active fractions and identification of the bacterial components/constituents within these fractions. Together, these results demonstrate that GMT has the potential to serve as an innate immune adjuvant (akin to vaccine adjuvants) that enhances the effect of immunotherapy for possibly many cancer types. Citation Format: Priscilla Del Valle, Gabriella Nguyen, Yongbin Choi, Parastoo Sabaeifard, Wenng li, Jake Lichterman, Laura Coughlin, Nicole Poulides, Angelica Sanjuan, Andrew Y. Koh. A novel gut microbiota therapeutic approach for enhancing immune checkpoint inhibitor therapy [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 1422.
Abstract 1434: Modeling the 3q26 OncCassette using genetically engineered mice
Authors: Kayleah M. Meneses, Yi Liu, Capella R. Weems, Lee Jamieson, Duy T. Nguyen, Verline Justilien, Nicole R. Murray, Alan P. Fields
Journal: Cancer Research (2024)

Abstract Lung squamous cell carcinoma (LUSC) is a devastating disease, accounting for ~30% of all lung cancer diagnoses and ~40,000 deaths annually in the United States alone. LUSC patients suffer from high prevalence of relapse and a dismal 5-year survival of only ~24%. The lack of animal models that reflect the salient features of human disease to assess the safety and efficacy of drugs, and to explore the underlying molecular mechanisms of LUSC tumor biology, is a major impediment for LUSC patients. We have identified concomitant 3q26 copy number gain (CNG) and TP53 loss as a defining genetic alteration present in ~90% of LUSC tumors. Furthermore, we have identified and characterized three 3q26 oncogenes (PRKCI, ECT2 and SOX2) that genetically and biochemically collaborate to drive LUSC tumor formation. Using syngeneic mouse modeling, we have demonstrated that coordinate overexpression of Prkci, Ect2 and Sox2, and loss of Trp53 in ex vivo cultures of lung basal stem cells (LBSCs; a cell of origin for LUSC) drives transformation of these cells into tumors of exclusively LUSC histopathology. These findings lead to the hypothesis that PRKCI, ECT2 and SOX2 represent a multigenic driver of 3q26 CNG-driven LUSC, which we term the 3q26 OncCassette. Based in these findings, we have developed and begun characterizing the first autochthonous genetically engineered mouse model (GEMM) to study 3q26 OncCassette-driven tumorigenesis. Our novel immune competent GEMM will provide critical insight into tumor initiation and progression of preneoplastic lesions to malignant LUSC and allow characterization of the immune landscape in these tumors. Citation Format: Kayleah M. Meneses, Yi Liu, Capella R. Weems, Lee Jamieson, Duy T. Nguyen, Verline Justilien, Nicole R. Murray, Alan P. Fields. Modeling the 3q26 OncCassette using genetically engineered mice [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 1434.
Abstract 7345: Double-strand break inference from mosaic chromosomal alterations
Authors: Abraham Dutch, Cody Bumgardner, Yasminka Jakubek
Journal: Cancer Research (2024)

Abstract Double-strand breaks (DSBs) can cause alterations and rearrangements in chromosomes leading to large structural mutations. There have been previous efforts to identify DSBs in tumors and utilize these as a measure of homologous repair deficiency and response to therapy. In contrast, DSBs have not been well characterized in non-tumor human tissues. To address this void, we explore the distribution of DSBs in hematopoietic stem cells (HSCs) through the analyses of mosaic chromosomal alteration (mCA) breakpoints. Specifically, this work explores the relationship between the likelihood of DSB occurrences and the chromosomes on which they occur. Using data from the UK Biobank, mCA breakpoints were labeled as either DSBs or nonDSBs by proximity to telomeres and centromeres. mCA calls from the UK Biobank were obtained from Loh et al 2020. The START_MB_RANGE and END_MB_RANGE fields were treated as two separate breakpoint events for each entry in the data. Each of these breakpoint ranges was checked to see if it was close to either of the telomeres or to the centromere. Those falling within one Mb were categorized as mCA breakpoints that were likely not a result of DSBs, but rather missegregation of chromosomes or chromosome arms. Ranges that met either of these conditions were labeled “nonDSB” while ranges that did not were labeled “DSB.” These labeled data were processed in R using the Hmisc package. The 1-alpha binomial probability was calculated for the total number of DSBs versus the total number of breakpoint events. The point estimate for each chromosome was plotted along with the upper and lower confidence intervals. This work investigates the properties of DSBs. It is important to note that the observed putative DSBs are not representative of the frequency of DSBs in HSCs, since the resulting mutations can have different impacts on cellular fitness. This point is highlighted by our finding of increased putative DSBs on chromosome 13, as copy number changes involving the 13q14 locus are well documented drivers of chronic lymphocytic leukemia. In this investigation we observe that the proportion of putative DSBs is not correlated with chromosome length (p = 0.2). This result is likely due to the differential fitness effect of mCAs. However, it may also reflect differences in the likelihood of DSBs across the genome. We are currently working on methods from Machine Learning to further understand if there are genetic features which can predict DSBs which give rise to mCAs in HSCs. Citation Format: Abraham Dutch, Cody Bumgardner, Yasminka Jakubek. Double-strand break inference from mosaic chromosomal alterations [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 7345.
Abstract 7354: Proteogenomic and metabolomic characterization of acute myeloid leukemia
Authors: Alec Chu, Yi Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James C. Pino, Camilo Posso, Leanne Henry, Lijun Chen, Ginny Xiaohe Li, Tung-Shing Mamie Lih, Yifat Geffen, Fengchao Yu, Li Ding, Gil Omenn, Chandan Kumar, Saravana M. Dhanasekaran, Elie Traer, Jeffrey W. Tyner, Hui Zhang, Tao Liu, Sara Gosline, Bing Zhang, Arul Chinnaiyan, Alexey I. Nesvizhskii, Marcin Cieslik
Journal: Cancer Research (2024)

Abstract Acute myeloid leukemia (AML) is a blood malignancy of poor prognosis with marked heterogeneity. To elucidate the underlying mechanisms that drive AML as part of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) effort, we performed comprehensive genomics, transcriptomics, proteomics including multiple post-translational modifications (phosphorylation, acetylation, and glycosylation), metabolomics, and lipidomics characterization of 173 treatment-naïve AML patients. Applying the similarity network fusion method on both transcriptomics and proteomics data, we identified 8 proteogenomic clusters. These clusters recapitulate specific recurrent mutations and established clinical subtypes available within the cohort. We used single-cell RNAseq data as a reference to perform immune component analysis for collected bulk samples. The result reveals that our proteogenomic clustering also captures the variations of AML differentiation hierarchies including CD14+ monocyte-like and GMP-like AML. To assess the complex disease nature of AML, we performed functional analysis for each cluster to reveal interplay between multiple genomic aberrations such as NPM1, FLT3-ITD, DNMT3A mutations, complex chromosomal alterations, and the leukemia cell differentiation. Importantly, the multi-omics analysis performed not only connects previously identified molecular drivers and cell differentiation variations within AML, but also links them with observed cancer metabolomic reprogramming with their drug response implications. Moreover, our study also identified site-specific post-translational modifications previously not known in AML, highlighting the valuable insights and clinical relevance of these newly identified clusters. Citation Format: Alec Chu, Yi Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James C. Pino, Camilo Posso, Leanne Henry, Lijun Chen, Ginny Xiaohe Li, Tung-Shing Mamie Lih, Yifat Geffen, Fengchao Yu, Li Ding, Gil Omenn, Chandan Kumar, Saravana M. Dhanasekaran, Elie Traer, Jeffrey W. Tyner, Hui Zhang, Tao Liu, Sara Gosline, Bing Zhang, Arul Chinnaiyan, Alexey I. Nesvizhskii, Marcin Cieslik, The CPTAC Consortium. Proteogenomic and metabolomic characterization of acute myeloid leukemia [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 7354.
Abstract 508: Determining the nuclear and cytoplasmic function of BMI-1 in diffuse intrinsic pontine glioma during M phase
Authors: Hao-Han Pang, Banlanjo Umaru, Shiva Senthil Kumar, Rachid Drissi
Journal: Cancer Research (2024)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) represents one of the most aggressive malignancies of the central nervous system, predominantly affecting children. DIPG is a particularly poor prognosis brain tumor with a median overall survival of less than 1 year. Hence, there is an urgent need to develop novel therapies that not only improve outcome but mitigate long-term complications in children with DIPG. The protein BMI-1, a critical component of the Polycomb Repressive Complex 1 (PRC1), is a proto-oncogene implicated in development, stemness of normal and malignant cells, and self-renewal. BMI-1 has emerged as a potential therapeutic target in DIPG; however, its role in DIPG tumorigenesis and progression remains elusive. We have previously shown that PTC596, a potent BMI-1 modulator, induces chromosome scattering, M phase cell-cycle arrest, BMI-1 phosphorylation and translocation to the cytoplasm leading to the inhibition of its PRC1 canonical function and cell death. These findings imply the induction of the spindle assembly checkpoint (SAC), thereby preventing mitotic exit followed by BMI-1 phosphorylation, probably at multiple sites, suggesting a survival role of BMI-1 in M phase in DIPG. The objective of the present study is to delineate the molecular pathways governing BMI-1 function during M phase and to establish the temporal sequence of these biochemical events related to BMI-1. Our data demonstrated that following PTC596 treatment, BMI-1 is actively transported from the nucleus to the cytoplasm. Furthermore, we observed colocalization of BMI-1 with COX4 in the mitochondria during M phase. Moreover, using Alphafold prediction model, BMI-1 could interact with CRM1 transporter. These findings suggest a potential PRC1-independent role of BMI-1 during early M phase required for DIPG proliferation. We are currently investigating potential pathways involved in BMI-1 nuclear-cytosol translocation through bioinformatic analyses, protein-protein interaction simulations, and pharmacological inhibitor assays. Collectively, these studies aim to elucidate the molecular mechanisms underlying BMI-1 functions in DIPG, thereby potentially paving the way for the development of targeted therapeutic strategies related to M phase progression. Citation Format: Hao-Han Pang, Banlanjo Umaru, Shiva Senthil Kumar, Rachid Drissi. Determining the nuclear and cytoplasmic function of BMI-1 in diffuse intrinsic pontine glioma during M phase [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 508.