tbuckley/cabot-search huggingface dataset:
Abstract 6865: Single cell analysis of melanoma reveals a prognostic myeloid cell associated with survival in melanoma with brain metastases
Authors: M. Usman Ahmad, Leong Heo, Ramesh V. Nair, Saurabh Sharma, Amanda Kirane
Journal: Cancer Research (2024)

Abstract INTRODUCTION: The interface of the innate and adaptive immune system are a critical factor in tumor behavior and responses to immunotherapy with myeloid cell behavior varying widely between various biogeographies. We sought to elucidate myeloid sub-type differences to characterize biology and support therapeutic strategies. METHODS: scRNA-seq of primary skin, acral, and metastatic melanoma were combined from 6 datasets with 126 patients for analysis. After integration, cells were analyzed with scCCESS, which uses an artificial neural network to reduce data and optimize k for k-means clusters. Myeloid clusters with analyzed with Recursive Partitioning Analysis (RPA), differential expressed gene (DEG) analysis, and pseudobulk comparison of RPA groups by gene expression. RESULTS: 102,971 single cells from 126 patients were analyzed to generate a cluster of 15,303 myeloid cells further subjected to clustering generating 6 cell types. RPA analysis of 6 myeloid populations in 46 patients with melanoma brain metastases generated 3 nodes with differing median survival months (17 vs 41 vs 57, p=0.01). There was a trend towards more adjuvant immunotherapy (p=0.057) and targeted therapy (p=0.019) in the worst surviving group. Myeloid type 1 cells showed increased expression of CLEC10A and AXL genes compared to all other cells (adj p = 0.000). Pseudobulk comparison of patient groups of genes showed CLEC10A was significant between all groups (p&amp;lt;0.05). CONCLUSIONS: Although there were no significant differences in neoadjuvant treatment, increased infiltration of CLEC10A myeloid cells showed improved survival in melanoma brain metastases. Targets of current therapies, such as AXL tyrosine kinase, have heterogenous presence across multiple cell types beyond tumors that may impact wide response variances, further study of these populations will have significant impact in both biomarker and therapeutics development. Citation Format: M. Usman Ahmad, Leong Heo, Ramesh V. Nair, Saurabh Sharma, Amanda Kirane. Single cell analysis of melanoma reveals a prognostic myeloid cell associated with survival in melanoma with brain metastases [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 6865.
Abstract 6584: Aberrant TRIM7 expression potentiates RACO-1 mediated proliferation and dysregulated interferon responsiveness in the setting of anti-PD-1 acquired resistance in cancer
Authors: Thuy-Ai Tran Nguyen, Marc Morra, Kevin Li, Ulhas Bhatt, Joseph Mwangi, Yisel Rivera-Molina, Nathan Oien, Julio Medina, Taylor H. Schreiber, George Fromm
Journal: Cancer Research (2024)

Abstract While checkpoint inhibitor treatment has extended the survival of many cancer patients, most initial responders will later develop disease progression through a variety of poorly understood acquired resistance mechanisms (CPI-AR). One such recently described mechanism involves the transcriptional hyperactivation of genes associated with interferon (IFN) signaling, JAK/STAT, and antigen processing/presentation pathways. Aberrant IFN regulation in the setting of AR suggests that tumor cell intrinsic mechanisms have conferred a growth advantage despite the presence of immune-mediated pressure unleashed by PD-1/L1 antibody blockade. Analysis of transcripts progressively upregulated during acquisition of AR in vivo and transcripts upregulated by IFN exposure of isolated AR cell lines in vitro identified the E3 ubiquitin ligase TRIM7 as a candidate mediator of the AR phenotype. A specific pocket on the PRY/SPRY domain of TRIM7 has been shown to bind viral peptides, resulting in ubiquitination and degradation as a mechanism to mitigate viral propagation. Here we describe the evaluation of small molecule inhibitors (SMI) designed to the TRIM7 PRY/SPRY viral-pocket domain, where binding specificity was confirmed using mass spec analysis. These SMI competitively inhibited TRIM7 mediated stabilization of RACO-1, resulting in decreased cancer cell proliferation which was associated with altered c-Jun/AP-1 transcription. TRIM7 SMI also disrupted STING and MAVS ubiquitination and restored IFN responsiveness and sensitivity to PD-1 inhibitor treatment. Finally, given the position of TRIM7 downstream of growth factor receptor and kras signaling, combination of TRIM7 inhibitors with kras, braf, and/or MEK inhibitors was shown to additively suppress proliferation of tumor cells with kras mutations. These results provide evidence that upregulation of TRIM7 mediates both a pro-proliferative and IFN resistant phenotype in the setting of CPI-AR, and that inhibition of TRIM7 with small molecule inhibitors may prevent or reverse AR to PD-1/L1 blockade. Citation Format: Thuy-Ai Tran Nguyen, Marc Morra, Kevin Li, Ulhas Bhatt, Joseph Mwangi, Yisel Rivera-Molina, Nathan Oien, Julio Medina, Taylor H. Schreiber, George Fromm. Aberrant TRIM7 expression potentiates RACO-1 mediated proliferation and dysregulated interferon responsiveness in the setting of anti-PD-1 acquired resistance in 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 6584.
Abstract 3733: Gut microbiota-dependent bile acidtaurodeoxycholic acid, TDCAfacilitates anti-tumor immune responses by modulating cytotoxic CD8 T cell immunity
Authors: Wenng li, Hesuiyuan Wang, Laura Coughlin, Nicole Poulides, Priscilla Del Valle, Jake Lichterman, Xiaowei Zhan, Chen Liao, Suzette N. Palmer, Xin Li, Andrew Y. Koh
Journal: Cancer Research (2024)

Abstract Gut microbiota are critical for effective immune checkpoint blockade therapy (ICT) for cancer. However, the underlying mechanisms by which gut microbiota and/or microbiota-derived metabolites augment antitumor response are largely unknown. Here, we utilized a preclinical melanoma (B16-F10) model and treated groups of mice (Jackson, C57BL/6J, female, 6-8 wks, n=14-26 per group) with seven distinct antibiotic treatments to induce unique gut microbiomes and metabolomes. Mice were then treated with ICT (anti-PD-1 and anti-CTLA-4), resulting in markedly heterogeneous tumor phenotypes (tumor volume and weight) as dictated by the specific antibiotic treatment. Using machine learning (e.g. random forest classifier), we identified metabolite candidates most strongly associated with ICT response (i.e. tumor volume and weight).One metabolite candidate, the bile acid taurodeoxycholic acid, TDCA, had previously been identified by my group as associated with anti-PD-1/anti-CTLA-4 response in human melanoma patients (PMID 28923537). Administration of TDCA alone is sufficient to overcome antibiotic-induced ICT hyporesponsiveness in mice. Utilizing both in vitro/ex vivo immune cell assays and in vivo preclinical models, we have validated that TDCA treatment directly boosted the antitumor cytotoxic CD8+ T cell responses (i.e. IFN-gamma production, anti-tumor cytotoxicity, tumor growth, etc.) without affecting innate immune responses. Bulk RNAseq of CD8 T cell analysis indicated that TDCA modulate CD8 T cell function through IFN pathway. Together, our findings suggest that the gut microbial metabolite TDCA could promote immunotherapy efficacy through regulation of CD8+ T cell immunity and has the potential to be utilized as a novel therapeutic agent to enhance ICT efficacy. Citation Format: Wenng li, Hesuiyuan Wang, Laura Coughlin, Nicole Poulides, Priscilla Del Valle, Jake Lichterman, Xiaowei Zhan, Chen Liao, Suzette N. Palmer, Xin Li, Andrew Y. Koh. Gut microbiota-dependent bile acidtaurodeoxycholic acid, TDCAfacilitates anti-tumor immune responses by modulating cytotoxic CD8 T cell immunity [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 3733.
Abstract 7042: Enhancing TCR T cell function in solid tumors through <i>in vivo</i> combinatorial screens and single-cell analysis
Authors: Dina Polyak, Jessica Fuhriman, Josephine Susanto, Allyson Merrell, Mandi Simon, Catherine Oh, Andrew Cordazo, David DeTomasso, Carla Tocchini, Vibhavari Sail, Eric Cui, Jeff Milush, Levi Gray-Rupp, Brendan Galvin, Christopher Murriel, Grace Zheng, Angela C. Boroughs, Pratiksha Thakore, Soyoung Oh, Jake Freimer, Bob Chen, Celine Eidenschenk, Emily Wheeler, Jacob Levine, Jan-Christian Huetter, Jill Schartner, Katie Geiger-Schuller, Orit Rozenblatt-Rosen, Sascha Rutz, Ira Mellman, W. Nicholas Haining
Journal: Cancer Research (2024)

Abstract The therapeutic potential of T cell therapies for treating solid tumors can be limited by intrinsic T cell exhaustion mechanisms and the suppressive tumor microenvironment. To better understand these challenges and identify genetic perturbations to enhance T cell functions, we developed in vivo exhaustion models and performed pooled CRISPR/Cas9-based screens with detailed characterization of T cell states through single cell RNA-sequencing (scRNA-seq). In vivo Xenograft exhaustion models were developed in the format of T cell receptor (TCR) T cells, with tumor cell lines expressing TCR-specific antigen (NY-ESO-1) respectively. Individual perturbations were introduced into T cells via non-viral editing and pooled before transferred into mice with established tumors of various sizes that provided continuous antigen exposure to drive exhaustion, while providing sufficient number of T cells from tumor and spleen tissues for scRNA-seq. The pooled CRISPR in vivo screens in human TCR T cells enabled us to evaluate T cell phenotypes resulting from gain-of-function, loss-of-function, or combinations of these modifications across a wide array of target genes. We identified known and previously uncharacterized combinatorial perturbations that were enriched or depleted and were associated with distinct transcriptional phenotypes over the course of chronic stimulation. This approach allows us to bridge the gaps in our understanding of how T cells can be reprogrammed to overcome exhaustion and function more effectively in the challenging environment of solid tumors. Citation Format: Dina Polyak, Jessica Fuhriman, Josephine Susanto, Allyson Merrell, Mandi Simon, Catherine Oh, Andrew Cordazo, David DeTomasso, Carla Tocchini, Vibhavari Sail, Eric Cui, Jeff Milush, Levi Gray-Rupp, Brendan Galvin, Christopher Murriel, Grace Zheng, Angela C. Boroughs, Pratiksha Thakore, Soyoung Oh, Jake Freimer, Bob Chen, Celine Eidenschenk, Emily Wheeler, Jacob Levine, Jan-Christian Huetter, Jill Schartner, Katie Geiger-Schuller, Orit Rozenblatt-Rosen, Sascha Rutz, Ira Mellman, W. Nicholas Haining. Enhancing TCR T cell function in solid tumors through in vivo combinatorial screens and single-cell analysis [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 7042.
Abstract 3768: Optimization of digital pathology through laser capture microdissection with a 405 nm laser
Authors: Thomas Philipson, Marissa Howard, Kevin Johnson, Amanda Still, Furkat Yunusov, Emanuel Petricoin, Virginia Espina, Noel Gonzalez, Alan Carpino, Lance Liotta
Journal: Cancer Research (2024)

Abstract Tumor cellular heterogeneity is a complex problem in cancer molecular diagnostics and personalized therapy. The tumor is a product of the different types and interactions of host and immune cells. Investigators have created a variety of methods to procure separate subpopulations of the tumor microenvironment for individual analysis. One of the most successful methods of this is laser capture microdissection (LCM). This method captures specific subpopulations of cells under direct microscopic visualization. This LCM technology has successfully been used for over 20 years, revealing a variety of insights into cancer pathogenesis and mechanisms of therapeutic response employed in numerous clinical trials. Nevertheless, there are two drawbacks to the current systems. For UV cutting (365 nm), the tissue is significantly damaged by the UV light energy. Infrared (808 nm) laser systems do not damage the tissue however, this method has low power and poor resolution. Our first hypothesis to be tested is that a new class of near UV 405 nm laser will have small capture areas approaching single cells while simultaneously preventing cellular damage. The second weakness of LCM is the requirement for an open-faced tissue section without a coverslip. Moreover, when visualizing the tissue of interest, the identification of regions of interest is obscured due to the refractive index mismatch between the laser microdissection cap and the tissue surface. We hypothesize that using a volatile organic compound with a refractive index similar to glass would elucidate the tissue region of interest to allow proper visualization. We successfully developed and tested a near 405 nm wavelength LCM system that utilizes a “liquid” coverslip to visualize the sample of interest with higher clarity, resolution, and contrast for immunohistochemistry, immuno-fluorescence, blood smear slides, and conventional hematoxylin-eosin tissue staining. Overall, these critical improvements LCM technology now allow for single-cell tissue capture, system automation, tissue visualization, and opens the door for artificial intelligence-assisted spatial profiling. Citation Format: Thomas Philipson, Marissa Howard, Kevin Johnson, Amanda Still, Furkat Yunusov, Emanuel Petricoin, Virginia Espina, Noel Gonzalez, Alan Carpino, Lance Liotta. Optimization of digital pathology through laser capture microdissection with a 405 nm laser [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 3768.
Abstract 7040: Mutations in cytoskeleton genes SPTAN1/SPTBN1 serve as novel predictive markers for immunotherapy against bladder cancer
Authors: Brian Yu-Ting Kuo
Journal: Cancer Research (2024)

Abstract Cancer progression is often driven by somatic mutations. Despite several well-known driver mutations, more evidence has shown that genetic alterations in cytoskeleton organization enhance tumor aggressiveness and promote cancer progression, suggesting their roles as potential drivers. In this study, pan-cancer genetic analyses by using TCGA cohorts, more frequent mutation events were found in cytoskeleton-related genes as compared to total annotated genes, especially in cancers derived from hollow organs. High-dimensional analysis of molecular alterations in cancer (HD-MAC) suggested gene mutations in SPTAN1 and its partner SPTBN1 as potential prognostic biomarkers for clinical outcomes of patients with bladder cancer. Gene knockdown in either SPTAN1 or SPTBN1, mimicking silencing mutations in cancer tissues, caused cell morphology changes, DNA breaks, and alternations in cytokine profiles via activating cGAS-STING mediated interferon signaling. Xenograft tumor models also indicate accelerated tumor growth in SPTAN1- or SPTBN1-silenced cells, suggesting a more advanced cancer type. Based on immune staining in both human and mouse samples, increased CD8+ T cell infiltration was in tumor lesions with mutations or truncations in SPTAN1/SPTBN1 genes. In addition, several known substitution mutations were found as potent neo-antigens based on MHC II binding prediction, which could be utilized as targets for immune checkpoint therapy. This study provides a novel insight into how the cytoskeleton can contribute to cancer progression and find out predictive biological indicators with therapeutic values. Citation Format: Brian Yu-Ting Kuo. Mutations in cytoskeleton genes SPTAN1/SPTBN1 serve as novel predictive markers for immunotherapy against bladder 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 7040.
Abstract 4906: Biopsy free virtual histology to discriminate benign from malignant squamous neoplasms
Authors: Nelly Kokikian, Rachel Wahhab, Jingxi Li, Stephanie Martin, David P. Beynet, Aydogan Ozcan, Phillip Scumpia
Journal: Cancer Research (2024)

Abstract Reflectance confocal microscopy (RCM) is a noninvasive optical imaging modality that allows for cellular-level resolution, in vivo images of skin without performing a traditional skin biopsy. RCM image interpretation currently requires specialized training to interpret the grayscale output images that are difficult to correlate with tissue pathology. Here, we use a deep learning-based framework that uses a convolutional neural network to transform grayscale output images into virtually-stained hematoxylin and eosin (H&amp;E)-like images allowing for the visualization of various skin layers, including the epidermis, dermal-epidermal junction, and superficial dermis layers. To train the deep-learning framework, a stack of a minimum of 7 time-lapsed, successive RCM images of excised tissue were obtained from epidermis to dermis 1.52 microns apart to a depth of 60.96 microns using the Vivascope 3000. The tissue was embedded in agarose tissue and a curette was used to create a tunnel through which drops of 50% acetic acid was used to stain cell nuclei. These acetic acid-stained images were used as “ground truth” to train a deep convolutional neural network using a conditional generative adversarial network (GAN)-based machine learning algorithm to digitally convert the images into GAN-based H&amp;E-stained digital images. We used the already trained machine learning algorithm and retrained the algorithm with new samples to include squamous neoplasms. Through further training and refinement of the algorithm, high-resolution, histological quality images can be obtained to aid in earlier diagnosis and treatment of cutaneous neoplasms. The overall goal of obtaining biopsy-free virtual histology images with this technology can be used to provide real-time outputs of virtually-stained H&amp;E skin lesions, thus decreasing the need for invasive diagnostic procedures and enabling greater uptake of the technology by the medical community. Citation Format: Nelly Kokikian, Rachel Wahhab, Jingxi Li, Stephanie Martin, David P. Beynet, Aydogan Ozcan, Phillip Scumpia. Biopsy free virtual histology to discriminate benign from malignant squamous neoplasms [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 4906.
Abstract 7054: <i>L1-ATP8B1</i> exacerbates high-level reduction-oxidation homeostasis to promote carcinogenesis via affecting PHB1 sumoylation in LUSC
Authors: Rui Zhang, Xiao Zhang, Zeguo Sun, Pengpeng Liu, Guidong Chen, Weijia Zhang, Jinpu Yu
Journal: Cancer Research (2024)

Abstract Long Interspersed Nuclear Element-1 (LINE-1, L1) plays important roles in carcinogenesis. However, the function of LINE-1 in lung squamous cell carcinoma (LUSC) remains unclear. Here we found that L1-ATP8B1 was overexpressed in LUSC patients with short survival and associated with mitochondrial dysfunction in both the TCGA dataset and the TJMUCH cohort. Overexpression of L1-ATP8B1 promoted cell proliferation and invasion in vitro and facilitated LUSC xenograft growth in vivo. L1-ATP8B1 affected mitochondrial complex enzyme I activity via affecting cardiolipin-dependent PHB1 sumoylation and promoting PHB1 ubiquitination, inducing high-level cellular reduction-oxidation (redox) homeostasis. Synergetic therapy with an L1 inhibitor and an antioxidant dramatically interfered with redox homeostasis and restored mitochondrial function, abolishing L1-ATP8B1-induced growth and metastasis of LUSC xenografts in vivo. In conclusion, we for the first time demonstrated that metabolic disorder plays a vital role in L1-related carcinogenesis and identified L1-ATP8B1 as a promising prognostic biomarker and therapeutic target for LUSC. Citation Format: Rui Zhang, Xiao Zhang, Zeguo Sun, Pengpeng Liu, Guidong Chen, Weijia Zhang, Jinpu Yu. L1-ATP8B1 exacerbates high-level reduction-oxidation homeostasis to promote carcinogenesis via affecting PHB1 sumoylation in LUSC [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 7054.
Abstract 7039: Leveraging single cell RNA-seq for uncovering immune landscape of hepatocellular carcinoma
Authors: Jian He
Journal: Cancer Research (2024)

Abstract The immune cell types as well as tumor microenvironment (TME) status may influence prognosis, metastasis, tumor progression, and clinical response to immunotherapies for cancer. Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China, however, the immune microenvironment of HCC, especially which caused by cancerogenic substance has not been clarified so far. In this study, we employed single-cell RNA sequencing (scRNA-seq) on diethylnitrosamine (DEN)-induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor-associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC TME. Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas (TCGA) HCC RNA-seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for the HCC. Citation Format: Jian He. Leveraging single cell RNA-seq for uncovering immune landscape of hepatocellular carcinoma [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 7039.