bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A029: Treatment-Specific Immune Phenotypes Identified by nELISA High-Throughput Proteomics Reveal Actionable Insights for Drug Discovery
Authors: Robichaud Nathaniel , Ongo Grant , Teahulos Ivan , Rho Woojong , Dagher Milad
Published: December 2023

Understanding tumor immunology requires high content tools that can capture the complex microenvironment, as well as high-throughput cell-based assays to rapidly screen compounds, antibodies, or cell therapies. Unfortunately, proteomics tools to investigate interactions between cancer and immune cells compromise either content or cost, limiting access to phenotypic data. To overcome this issue, we developed the nELISA: a high-throughput miniaturized ELISA quantifying 191 cytokines, chemokines, proteases and growth factors, at 10x-reduced cost compared to previous tools, and applied it to cell based models to demonstrate its ability to characterize immune phenotypes in co-culture systems. We ran the largest PBMC secretome screen to date, in which ~10,000 PBMC samples were treated with various inflammatory stimuli, and were further perturbed with a selected library of 80 recombinant protein “perturbagens”. 191 secreted proteins were profiled in all samples, resulting in ~2M datapoints. The nELISA profiles were able to capture phenotypes associated with specific stimulation conditions, individual donors, and potent cytokine perturbagens. By compensating for stimulation and donor differences, we clustered perturbagens according to their effects on PBMC secretomes. As expected, perturbagens such as IFN gamma and IL-4 led to well-established Th1 or Th2 responses, respectively, and clustered with perturbagens involved in these phenotypes. Novel phenotypic effects were also identified, such as distinct responses to the near identical CXCL12 alpha and beta isoforms. Interestingly, we observed important similarities between PBMC responses to the cytokine drugs IFN beta and IL-1 Receptor antagonist, supporting the use of the latter as a replacement for the former in certain indications. These findings highlight the ability of the nELISA to capture actionable insights from high-throughput screens, and demonstrate its applicability to SAR studies and drug repurposing screens. Thus, the nELISA is a powerful tool for immunotherapy drug discovery, and we will expand upon its use for target identification, in vitro pharmacology, predicting patient response to therapy, as well as characterizing the potential of iPSC- or donor-derived material for cell therapy.

Citation Format: Nathaniel Robichaud, Grant Ongo, Ivan Teahulos, Woojong Rho, Milad Dagher. Treatment-Specific Immune Phenotypes Identified by nELISA High-Throughput Proteomics Reveal Actionable Insights for Drug Discovery [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A029.
Abstract A030: Blood-based screening panel for lung cancer based on clonal hematopoietic mutations in tumor infiltrating immune cells
Authors: Anandakrishnan Ramu , Shahidi Ryan , Dai Andrew , Antony Veneeth
Published: December 2023

Early detection can significantly reduce mortality due to lung cancer. However, the high cost of the currently approved screening protocol has limited its uptake. Presented here is a blood-based screening panel based on clonal hematopoietic mutations. Mutations in tumor cells that inhibit immune destruction have been extensively studied. However, mutations in immune cells that may prevent an effective anti-tumor immune response remain relatively unstudied. Animal model studies suggest that clonal hematopoietic mutations in tumor infiltrating immune cells can modulate cancer progression, representing potential predictive biomarkers. The goal of this study was to determine if the clonal expansion of these mutations in blood samples could predict the occurrence of lung cancer. We identified a set of 98 potentially pathogenic clonal hematopoietic mutations in tumor infiltrating immune cells. A logistic regression machine learning model based on these mutations correctly classified lung cancer and non-cancer blood samples with 94.12% sensitivity (95% Confidence Interval: 92.20-96.04%) and 85.96% specificity (95% Confidence Interval: 82.98-88.95%) in a test set of 578 lung cancer and 545 non-cancer samples from 18 different cohorts. More importantly, 89.98% of the cancer cases were unambiguously predicted with probability of cancer >0.90 and 74.86% of the non-cancer cases with probability of cancer <0.10. These results suggest that it may be possible to develop an accurate blood-based lung cancer screening panel. Unlike most other “liquid biopsies” currently under development, the assay presented here is based on standard sequencing protocols and uses a relatively small number of rationally selected mutations as predictors.

Citation Format: Ramu Anandakrishnan, Ryan Shahidi, Andrew Dai, Veneeth Antony. Blood-based screening panel for lung cancer based on clonal hematopoietic mutations in tumor infiltrating immune cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A030.
Abstract A033: Secretogranin V as a Potential Biomarker for Esophageal Squamous Cell Carcinoma
Authors: Hamrah Mohammad Hussain
Published: December 2023

Background: Oesophageal squamous cell carcinoma (ESCC) remains one of the most poorly diagnosed and deadly cancers worldwide. Identification of biomarkers to accurately predict the risk of recurrence and survival after surgery is therefore crucial to improving patient outcomes. This study examined the expression of Secretogranin V (SCG5) and its correlation with the prognosis of patients with ESCC.

Methods: Transcription levels of SCG5 were evaluated in 22 cell lines of ESCC. The biological roles of SCG5 in cell invasion, proliferation, and migration were verified by small interfering RNA- mediated knockdown experiments. The expression of SCG5 was measured in 165 ESCC tissues by using quantitative reverse-transcription (qRT)-PCR, and its association with clinicopathological parameters was analyzed.

Results: SCG5 mRNA expression levels varied widely in ESCC cell lines. Knockdown of SCG5 expression significantly suppressed cell invasion, proliferation, and migration of ESCC cells in vitro. Analysis of clinical specimens revealed that the expression of SCG5 mRNA was overexpressed in the ESCC compared to the adjacent normal oesophageal tissues. The high SCG5 expression group had significantly shorter overall and disease-free survival times. In the multivariable analysis, the high expression of SCG5 was determined to be an independent poor prognostic factor.

Conclusion: SCG5 may have a significant role as a diagnostic and prognostic biomarker for ESCC.

Citation Format: Mohammad Hussain Hamrah. Secretogranin V as a Potential Biomarker for Esophageal Squamous Cell Carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A033.
Abstract A052: Comprehensive EBV-specific T cell profiling and multi-omics analysis of nasopharyngeal carcinoma CD8 T cells reveals novel cancer-associated phenotype
Authors: Kumar Nandita , Nguyen Long , Jani Saumya , Lim Darren WT , Yeong Joe PS , Chua Melvin LK , Jain Amit , Newell Evan W
Published: December 2023

Nasopharyngeal carcinoma (NPC) is a high mortality, Epstein-Barr virus (EBV)-driven cancer with limited treatment options. Although EBV is highly antigenic and detectable in nearly all NPC tumor cells, it remains unclear why NPC tumors evade immune targeting despite high levels of immune infiltration. Here, we investigate the phenotypes of peripheral EBV-specific T cells with the purpose of identifying clinically relevant, cancer-associated EBV-specific T cell phenotypes. We developed a 34-marker mass cytometry and multiplexed MHC-I tetramer panel to detect and phenotype CD8 T cells of up to 55 antigen-specificities, including EBV and other known viral and cancer-antigen epitopes. We used this approach to profile peripheral blood mononuclear cells (PBMCs) from treatment-naïve NPC patients (n=51). Compared to other antigen-specific T cells detected in NPC patients and EBV-specific T cells in healthy individuals, EBV-specific T cells in NPC patients expressed high levels of activation markers (CD38, HLA-DR), co-inhibitory markers (CD39, TIGIT, PD-1), and migratory markers (ITB7, CD103). Using unsupervised clustering, we found that the frequency of EBV-specific T cells in a phenotypic cluster characterized by high CD103, CD39, HLA-DR, and CD38 expression positively correlated with plasma EBV-DNA titer and gross tumor volume. Remarkably, we observed that regardless of antigen specificity, NPC patients had a higher frequency of total CD8 T cells with this activated/exhausted cluster phenotype. CD8 frequencies of this cluster were also positively correlated with plasma EBV-DNA titer and stage (TNM). To investigate the gene expression profiles and TCR clonal diversity of this cancer-associated phenotype, we performed single-cell multi-omics analysis on peripheral CD8 T cells from NPC patients (n=17). We identified that cell subsets within this phenotype had distinct gene expression patterns indicative of potential associations with the tumor and we also assessed the clonality of these subpopulations. Overall, this study identified a unique cancer-associated peripheral EBV-specific T cell phenotype in the context of nasopharyngeal carcinoma that is positively correlated with advanced disease. Frequencies of peripheral T cells with this phenotype could also be useful as a blood-based prognostic marker for NPC.

Citation Format: Nandita Kumar, Long Nguyen, Saumya Jani, Darren WT Lim, Joe PS Yeong, Melvin LK Chua, Amit Jain, Evan W Newell. Comprehensive EBV-specific T cell profiling and multi-omics analysis of nasopharyngeal carcinoma CD8 T cells reveals novel cancer-associated phenotype [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A052.
Abstract B001: Harnessing invariant natural killer T cell cytotoxicity for cancer therapy
Authors: Herbozo Carolina de Amat , Wong Stephanie , Kuypers Meggie , Matthews Jessica , Baranek Thomas , Crome Sarah , Sacher Adrian , Paget Christophe , Mallevaey Thierry
Published: December 2023

Cytotoxic cells are major effectors in adoptive cell transfer (ACT) cancer therapies. Although autologous conventional T cells are commonly used in ACT therapies, other types of cells, such as invariant natural killer T (iNKT) cells, have become attractive for the design of off-the-shelf ACT therapies. Unlike conventional T cells, iNKT cells react to glycolipid antigens presented by CD1d, a non-polymorphic MHC I-like molecule. Based on their cytokine profile and transcription factor expression, three main helper iNKT subsets have been described in mice: iNKT1, iNKT2, and iNKT17. In addition, the cytotoxic response of iNKT cells has been reported, but this function is less characterized. In a previous transcriptomic study, we have shown that the iNKT1 subset is heterogeneous and it comprises two main clusters: iNKT1b, enriched in genes related to T helper 1, and iNKT1c, characterized by a cytotoxic gene profile. Here, we demonstrated that iNKT1c cells exhibit higher in vitro specific killing activity against EL4 tumor cells compared to iNKT1b cells. We identified IL-15 as one of the factors that boosts the cytotoxic functions of iNKT1c cells. Moreover, adoptive cell transfer of iNKT1c cells in mice previously injected with B16F10 melanoma cells resulted in reduced metastatic lung nodules. We also explored the presence of a distinct cytotoxic iNKT cell subset in humans by spectral flow cytometry and clustering analysis. From PBMCs of healthy donors, we identified a population of CD57+Tbethi iNKT cells that show a cytotoxic profile. Interestingly, this population can also be found infiltrating tumors in lung cancer patients. This study unraveled bona fide cytotoxic iNKT cells and provides insights for the design of future cancer therapies.

Citation Format: Carolina de Amat Herbozo, Stephanie Wong, Meggie Kuypers, Jessica Matthews, Thomas Baranek, Sarah Crome, Adrian Sacher, Christophe Paget, Thierry Mallevaey. Harnessing invariant natural killer T cell cytotoxicity for cancer therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B001.
Abstract B009: GBM cells mimic regulatory T cell function to protect the CSC pool from immune surveillance in recurrent GBM
Authors: Lopez-Bertoni Hernando , Sall Sophie , Khela Harmon , Korleski Jack , Luly Katherine , Johnson Maya , Johnson Amanda , Green Jordan , Laterra John
Published: December 2023

Glioblastoma (GBM) is the most lethal and aggressive form of brain cancer, with incredibly high recurrence rates and virtually no long-term survival. Despite our growing understanding of GBM at the molecular level, we still don’t fully comprehend the molecular mechanisms driving recurrence in GBM. Current knowledge indicates that Glioma Stem Cells (GSCs) drive a resistant cell phenotype in GBM. Understanding the molecular events coordinated by GSCs leading to therapy-resistance can provide key advancements on how we treat recurrent GBM (rGBM). Mechanisms of GSC immune escape are considered fundamental to clinical GBM growth and recurrence. The cross talk between cancer cells and the immune system is now classified as a hallmark of cancer. The current dogma is that cancer cells, including GSCs, influence recruitment of immune-suppressive cell subsets to tumor tissue, however how subsets of GSCs mimic this immune-suppressive effect within the tumor microenvironment remains to be elucidated. Single-cell RNA sequencing analysis of GBM neurospheres revealed a previously unrecognized Oct4/Sox2high/FOXP3− cell subpopulation with high expression of TGFb1, CD39, CD73, PD-L1, and Galectin-1, a gene expression fingerprint typically associated with regulatory T cell (Tregs) and their immune suppressive functions within the tumor microenvironment. Bioinformatics analysis of public databases shows that the above-mentioned genes are enriched in the mesenchymal GBM subtype and highly correlated with TGFb type II receptor (TGFBR2) expression in clinical GBM. Mechanistically, we show that blocking TGFBR2 or XBP1 signaling, key intermediary of this process, counteracts the immune-suppressive phenotype of rGBM cells by restoring CD4 and CD8 tumor killing capacity and reversing exhaustion. By combining miRNA-based network analysis and advanced nanoparticle formulation for miRNA delivery we show that miR-16/124-3p effectively target all nodes of this immunosuppressive axis successfully blocking the immunosuppressive nature of rGBM cells. This research provides the first description of such neoplastic cells in any malignancy and has high potential translational impact since targeting these tumor cell subsets and their immunosuppressive mechanisms may be critical to the successful development of GBM immunotherapies.

Citation Format: Hernando Lopez-Bertoni, Sophie Sall, Harmon Khela, Jack Korleski, Katherine Luly, Maya Johnson, Amanda Johnson, Jordan Green, John Laterra. GBM cells mimic regulatory T cell function to protect the CSC pool from immune surveillance in recurrent GBM [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B009.
Abstract B013: Investigating the role of LINE-1 ORF1 protein in a syngeneic mouse melanoma model
Authors: Nandani Raj , An Wenfeng
Published: December 2023

Long interspersed element type 1 (LINE-1) is a class of transposable elements that make up 17% of human genome. Somatic LINE-1 insertions promote genomic instability and have been implicated in the evolution of various human cancer types. A full-length LINE-1 has two open reading frames (ORF1 and ORF2) that encode proteins essential for its replication in the genome. It has been well documented that LINE-1 ORF1 protein (ORF1p) is overexpressed in tumor tissues as compared to non-tumor tissues. However, whether ORF1p itself is oncogenic remains controversial. Downregulation of ORF1p has been shown to reduce cancer cell proliferation and metastasis. ORF1p has also been associated with the modulation of tumor microenvironment and activation of oncogenic pathways by interacting with cellular proteins. We are interested in the role of LINE-1 ORF1p in a syngeneic mouse melanoma model. B16-F10 is a mouse melanoma cell line derived from a C57BL/6 mouse. It had an undetectable level of ORF1p by Western blot. To investigate the effect of ORF1p overexpression in vitro and in vivo, we started with establishing ORF1p expression in B16-F10 cells. We utilized the Sleeping Beauty gene delivery system to make single-cell clones expressing the protein. Cell proliferation and migration assays give insight into the effect of ORF1p overexpression in vitro. Growth of the parental and ORF1p-expressing B16-F10 cells in C57BL/6 mice informs the effect of ORF1p overexpression in vivo. This study represents an important first step to establishing the role of ORF1p in melanoma, a common cancer worldwide.

Citation Format: Raj Nandani, Wenfeng An. Investigating the role of LINE-1 ORF1 protein in a syngeneic mouse melanoma model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B013.
Abstract B020: Hypoxia as tumor-intrinsic regulator of Flt3L production by NK cells
Authors: van den Bijgaart Renske J.E. , Avanessian Shayan C. , Chew Nayvin W. , Tang Thao T. , Barry Kevin C.
Published: December 2023

Natural killer (NK) cell abundance in the tumor correlates with increased immunotherapy responses and better survival in cancer patients. As their name suggests, NK cells can control tumors through their direct cytotoxicity, but also play an important part in regulating immune responses through their immunomodulatory production of cytokines and chemokines. We recently discovered that NK cells control immunotherapy responses through their production of a cytokine called FMS-like tyrosine kinase 3 ligand (Flt3L) in the tumor, which regulates type 1 conventional dendritic cell (cDC1) abundance. However, the mechanisms regulating NK cell phenotype and function, including Flt3L production, in the tumor remain unknown. Here, we define tumor cell-intrinsic mechanisms that control these protective NK cell functions in the tumor. Across eight mouse melanoma tumor models, we found two genetically distinct murine ectopic tumors (referred to as Mel1 and Mel2) that are similarly infiltrated with total NK cells, but have distinct skewing of NK cell phenotypes and differential production of Flt3L, correlating with differences in cDC1 abundance. Pathway analysis of differentially expressed genes in tumor cells from these two models found a significant increase in hypoxia signaling in Mel1 tumors. Using an in vivo hypoxia tracer and in vitro hypoxia chamber studies, we found that NK cells in Mel1 tumors experience more severe hypoxia and that NK cells produce significantly less Flt3L under hypoxic conditions (1% O2) compared to NK cells in normoxic conditions (21% O2). Our findings suggest that hypoxia is a tumor-intrinsic regulator of Flt3L production by NK cells and highlight a previously unknown inhibitory pathway within the tumor that can shape the protective immunomodulatory effects of NK cells.

Citation Format: Renske J.E. van den Bijgaart, Shayan C. Avanessian, Nayvin W. Chew, Thao T. Tang, Kevin C. Barry. Hypoxia as tumor-intrinsic regulator of Flt3L production by NK cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B020.
Abstract B026: The senescent tumor cells evade the immune system by secreting SASPs in colorectal cancer
Authors: Park Tae Jun , Park Soon Sang
Published: December 2023

In colorectal cancer, the transition of cancer cells from an adenoid to a collective invasion morphology, ultimately leading to a partial epithelial-mesenchymal transition phenotype at the invasive front, has been observed. Through comprehensive gene expression analysis, we identified distinct gene expression patterns between cancer cells at the invasive front and those in the central region, with cellular senescence playing a pivotal role in this transition. Trajectory analysis revealed a gradual transformation of non-senescent tumor cells in the central region into senescent cells at the invasive front, accompanied by altered gene expression patterns. Furthermore, we observed a progressive increase in the expression of CXCL12 and CSF1 at the invasive front. Senescent tumor cells were found to impair the directional migration of CD8+ T cells by secreting high concentrations of CXCL12. Additionally, CSF1 secreted by senescent tumor cells promoted the differentiation of monocytes into M2 macrophages, which subsequently inhibited CD8+ T cell activation. Importantly, inhibiting CXCL12 secretion from senescent tumor cells enhanced T cell infiltration and resulted in reduced tumor number and size. These findings highlight the generation of a cytokine barrier by senescent tumor cells, which serves to protect non-senescent tumor cells from immune attack. Moreover, this study identifies senescent tumor cells as a potential target for overcoming immunotherapy resistance in colorectal cancer. The development of interventions that disrupt the cytokine barrier and enhance T cell infiltration holds promise for improving the efficacy of immunotherapeutic approaches in the treatment of colorectal cancer.

Citation Format: Tae Jun Park, Soon Sang Park. The senescent tumor cells evade the immune system by secreting SASPs in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B026.
Abstract B028: WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in small cell lung cancer
Authors: Sen Triparna
Published: December 2023

Background: Small cell lung cancer (SCLC) is a poorly immunogenic, high-grade neuroendocrine carcinoma arising in the lung. Immune checkpoint blockade (ICB) added to chemotherapy is now the standard upfront therapy for SCLC but leads to a modest increase in overall survival and progression-free survival. These modest benefits underscore the critical need to identify pathways and targets that can durably enhance the antitumor responses of ICB in SCLC. SCLC is characterized by a ubiquitous loss of TP53 which disrupts the G1-S cell cycle checkpoint and as a result, most SCLC is dependent on G2-M cell cycle checkpoint regulators including WEE1. We and others have shown that DNA damage response (DDR) components are overexpressed in SCLC and targeting DDR could be an effective therapeutic strategy in SCLC.

Methods: In this study, we have performed WEE1 inhibition either alone or in combination with PD-L1 blockade in a panel of SCLC models.

Results: We demonstrate that inhibition of WEE1 induces G2/M cell cycle arrest, DNA damage, and cytosolic DNA accumulation in SCLC models. We further show that WEE1 targeting activates the STING-TBK1-IRF3 pathway which increases type I interferons (IFN-α and IFN-β) and pro-inflammatory chemokines (CXCL10 and CCL5), facilitating an immune response via CD8+ cytotoxic T-cell infiltration. We further show that WEE1 inhibition concomitantly activates the STAT1 pathway, increasing IFN-γ and PD-L1 expression. Consistent with these findings, combined WEE1 inhibition (AZD1775) and PD-L1 blockade caused remarkable tumor regression, activation of type I and II interferon pathways, and infiltration of cytotoxic T-cells in multiple immunocompetent SCLC genetically engineered mouse models, including an aggressive model with stabilized MYC.

Conclusions: Our study demonstrates the cell-autonomous and immune-stimulating activity of WEE1 inhibition in SCLC. Given the increasing importance of immunotherapy for the management of SCLC and that WEE1 inhibitors are already in clinical trials, combining a WEE1 inhibitor with PD-L1 blockade may offer a particularly attractive strategy for the treatment of SCLC and contribute to the rapid translation of this combination into the clinic.

Citation Format: Triparna Sen. WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B028.
Abstract B031: A tale of cancer cell death and immunity
Authors: Workenhe Samuel T
Published: December 2023

Patients with tumors that have substantial T cell infiltration benefit from immunotherapy to survive longer. However, several tumor types lack T cells within the tumor and are hence refractory to immunotherapy. Therefore, therapies that render immune-evading cancers susceptible to cytotoxic T cells are highly desirable. We and others have shown that certain types of cancer cell death can kickstart multiple aspects of the anticancer immunity cycle to inflame “cold” tumors. These immunological outcomes were driven by the secretome emitted by a variety of stress and programmed cell death. Many cytotoxic chemoradiotherapies simultaneously activate multiple types of stress and cell death. Hence, it has been a major clinical challenge to identify what specific types of cancer cell death are efficient at eliciting durable anticancer immunity. The overall goal of my lab’s research program is to identify what types of cancer cell death initiate effective anticancer immunity and expand therapeutic approaches to deadly cancers such as pancreatic and brain cancer. Since the start of my lab in September 2020, we have created synthetic models of cell death where inducible expression of cell death executioner proteins activates distinct types of cancer cell death such as apoptosis, necroptosis, and pyroptosis. Using these models, we identified that the secretomes of apoptotic, necroptotic, and pyroptotic tumors display remarkable differences in previously established markers of immunogenic cell death and novel secretomes as identified by mass spectrometry. In follow-up, in vivo studies, we identified differences in the activation and maturation patterns of antigen-presenting cells, such as type I conventional dendritic cells (cDC1). Consistent with the differences in cDC1 functionality we identified differences in the magnitude, diversity, and functionality of effector CD8+ T cells. All these immunological differences contributed to significant differences in the anticancer protective activity of distinct cancer cell death types. During my talk, I will be presenting these findings and discussing how these basic findings can be integrated into translational platforms for the management of non-T cell inflamed pancreatic and brain tumors.

Citation Format: Samuel T Workenhe. A tale of cancer cell death and immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B031.
Abstract B035: The contribution of inflammasomes and cGAS-STING in RT-induced cell fate
Authors: Ha Cindy T , Nicholson-Puthenveedu Shirony , Harding Shane M
Published: December 2023

Radiotherapy (RT) is a curative treatment modality for many solid cancers. Our group has previously demonstrated that activation of the cGAS-STING pathway by RT induces inflammatory cytokine production and subsequent stimulation of anti-tumour immunity in concert with immune checkpoint blockade treatment. We have identified three other proteins that contribute to inflammatory signalling after RT: AIM2 (Absent in Melanoma 2), NLRP3 (NOD-Like Receptor Pyrin Domain-Containing 3), and IFI16 (Interferon Gamma Inducible Protein 16). Each of these proteins contribute to form distinct protein complexes called inflammasomes that, like cGAS-STING, sense cytoplasmic DNA. Little is known about how inflammasome signalling may change after RT, or how inflammasomes may influence RT-ICB induced anti-tumour immunity. We hypothesize that RT induces inflammasome signalling to influence specific gene expression and cytokine profiles, in tandem with alterations in cellular fate with implications for systemic anti-tumour immunity triggered by radiotherapy. We will present ongoing work in which we show that pharmacological or genetic disruption of inflammasomes alters cytokine production post-RT. We also demonstrate that manipulation of cell fate through senolytic therapy or manipulation of caspase activity alters the balance of cytokine production post-RT. Together our data strongly implicates the role of several inflammasome complexes in the response of epithelial cells to RT. Our work will also highlight the possible crosstalk between the cGAS-STING pathway and inflammasome complex pathway, both triggered by RT. Understanding and subsequent manipulation of cell fate, in part through inflammasome and cGAS-STING mediated activity, may be a therapeutic strategy to influence treatment responses, such as anti-tumour immunity, in cancer.

Citation Format: Cindy T Ha, Shirony Nicholson-Puthenveedu, Shane M Harding. The contribution of inflammasomes and cGAS-STING in RT-induced cell fate [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B035.
Abstract B047: Tertiary lymphoid structures and B cells signatures determine clinically relevant T cell phenotype in ovarian cancer
Authors: Moserova Irena Kusova , Kasikova Lenka , Rakova Jana , Tomankova Jana , Henser Michal , Lanickova Tereza , Mojzisova Katerina , Drozenova Jana , Laco Jan , Rob Lukas , Halaska Michael , Ryska Ales , Lischke Robert , Vachtenheim Jiri , Cibula David , Galluzzi Lorenzo , Spisek Radek , Fucikova Jitka
Published: December 2023

Tertiary lymphoid structures (TLSs) are ectopic lymphoid formations that arise at sites with persistent inflammatory conditions, including tumors. TLSs are composed predominantly of B cells, T cells, and CD21+ CD23+ follicular dendritic cells and exhibit different levels of the organization, ranging from locally concentrated aggregates of immune cells to well-defined B cell follicles to mature follicles with germinal center formation. Supporting key relevance for TLSs in natural and immunotherapy-driven immunosurveillance, intratumoral TLS density has been associated with improved disease outcome and response to cancer immunotherapy, mainly check-point inhibitors (ICIs) in solid carcinomas. Here, we demonstrate that compared to the immunologically hot tumors like non-small cell lung carcinoma (NSCLC), human high-grade serous ovarian carcinoma (HGSOC) contains only a limited number of TLS with germinal center formation. In parallel, TLS frequency and maturation positively correlate with progenitor stem-like CD8+ T cell phenotype. In line with this notion, B cell depletion in HGSOC biopsies promoted terminally exhausted, poorly ICI-sensitive CD8+ T cells, suggesting a critical role of intratumoral B cells in maintaining T cell effector functions. These findings point to key numerical and functional differences between mature TLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative ICI-based immunotherapies for patients with HGSOC.

Citation Format: Irena Kusova Moserova, Lenka Kasikova, Jana Rakova, Jana Tomankova, Michal Henser, Tereza Lanickova, Katerina Mojzisova, Jana Drozenova, Jan Laco, Lukas Rob, Michael Halaska, Ales Ryska, Robert Lischke, Jiri Vachtenheim, David Cibula, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova. Tertiary lymphoid structures and B cells signatures determine clinically relevant T cell phenotype in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B047.
Abstract PR01: Regulation of exhausted CD8+ T cell differentiation by IKZF transcription factors
Authors: Reading Sinead M , Munoz Isabelle , de Menezes Maria Nogueira , Saw Nicole Y.L , Ambani Krutika , Ahn Antonio , Nussing Simone , Roth Sara , Sampurno Shienny , Ramsbottom Kelly M , Trapani Joseph A , Good-Jacobson Kim L , Johnstone Ricky W , Goel Shom , Beavis Paul A , Parish Ian A
Published: December 2023

CD8+ T cells are indispensable for pathogen and tumor clearance, although can induce immunopathology if left unrestricted. T cell exhaustion, progressively programmed in the context of persistent antigen exposure, ensures partial control while mitigating immunopathological risk. However, exhaustion is characterized by curtailed proliferative capacity, cytokine production and cytotoxic functions, which tumors and chronic pathogens exploit to persist. As such, transiently disrupting exhaustion has emerged as a therapeutic strategy for treating cancer. Exhausted cells transition through a range of differentiation states, from stem-like progenitors that mediate response to checkpoint blockade, through to terminal effector or exhausted cells. Understanding the molecular pathways moderating the exhausted states and promoting terminal exhaustion is essential for augmenting cancer immunotherapy. We identify IKZF transcription factors, Ikaros (IKZF1), Helios (IKZF2) and Aiolos (IKZF3), as key mediators of T cell exhaustion, using gene knock-out mice and a CRISPR-mediated genetic knock-out system in both chronic infection and tumor models. IKZF1 and IKZF3 are critical regulators of exhausted subset expansion, retention, phenotype and cytokine function. Strikingly, dual IKZF1 and IKZF3 ablation boosts the response of anti-tumor and anti-viral exhausted T cells, potentially via the formation of atypical exhausted T cell populations and the enrichment of functional exhausted subsets. Cumulatively, our data highlight a novel role for IKZF transcription factors in biasing exhausted T cell differentiation and provides potentially important clinical implications, directing future cancer immunotherapies targeting T cell exhaustion.

Citation Format: Sinead M Reading, Isabelle Munoz, Maria Nogueira de Menezes, Nicole Y.L Saw, Krutika Ambani, Antonio Ahn, Simone Nussing, Sara Roth, Shienny Sampurno, Kelly M Ramsbottom, Joseph A Trapani, Kim L Good-Jacobson, Ricky W Johnstone, Shom Goel, Paul A Beavis, Ian A Parish. Regulation of exhausted CD8+ T cell differentiation by IKZF transcription factors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr PR01.
Performance analysis of protection devices in electrical power distribution system: Eko Electricity Distribution Company as a case study
Authors: Awuwoloye Philip Oludele , Adejumobi Isaiah Adediji , Adebisi Oluwaseun Ibrahim , Ismaila Salami Olasunkanmi
Published: December 2023

One of the major challenges hindering the effective operation of the electricity distribution system is the malfunctioning of the protection scheme. Therefore, in this study, the performance of an interrupter (oil circuit breaker (OCB)) on the Eko Electricity Distribution Company (EKEDC) network was assessed. Five-year outage data (2014 to 2018) regarding tripping of the interrupter on fault and health conditions were collected from the EKEDC Agbara/Badagry Business Unit. The tripping frequency was compared. Inspection of selected OCBs within the considered network was conducted over the study period. A breakdown voltage (BDV) test was carried out on six oil samples each for 11 and 33 kV OCB using Megger OTS60PB. The highest tripping frequency of 75 and 10 were observed in 2014 and 2018 respectively when the interrupter tripped on fault and healthy conditions. The lowest tripping frequency was, however, observed in 2018 with values of 46 and 7 respectively when the interrupter tripped on fault and healthy conditions. The inspection conducted revealed carbonized OCB contacts. The BDV test showed that two oil samples each violated the standard value of 40 kV for 11 and 33 kV OCBs respectively. This study indicated that the defective oil samples required filtration or complete replacement.
Data mining applied about state madrasah using sentiment analysis on Twitter in Indonesian perception
Authors: Mahsusi Mahsusi , Hudaa Syihaabul , Nuryani Nuryani , Bahtiar Ahmad
Published: December 2023

Indonesian people prefer private schools with high prices, which is one of the exciting things to study. In fact, in the modern era, public schools have competed with private schools with international categories. The problem in public schools is the parent's perspective on the quality of education in public schools, especially public madrasahs. In addition, cases such as bullying and violence between schools. People on Twitter also have various perceptions of public madrasas, which are considered to have religiosity. This research uses the keywords public madrasah, quality management, and quality taken from Twitter using the Orange application. The amount of data in this research is 300 tweets from Twitter. As a result, there are both negative and positive sentiments toward public madrasas. However, the negative sentiment is higher than the positive sentiment. This means parents have more trust in private schools than in public madrasahs.
MCDM-AHP and PROMETHEE methods integrated for base service strategy vendor evaluation and selection
Authors: Akmaludin Akmaludin , Samudi Samudi , Palasara Nicodias , Harmono Feri Prasetyo , Widianto Kudiantoro , Muharrom Muhammad
Published: December 2023

Business competition is very important in controlling product-savvy customers. Strong basic service techniques will be the main factor that binds vendors as the final destination in the supply chain through the strength of business network processes. This research aims to create a strategic basis for evaluating and selecting vendors through the integration process services of the multi-criteria decision-making method analytic hierarchy process (MCDM-AHP) and preference ranking organization method for enrichment evaluation (PROMETHEE) methods. Empirical studies show how this approach can provide optimal decision support for the vendor evaluation and selection process. Eight different types of criteria are required in its apps and must be realized as a barometer of the strategic basis for selecting vendors so that business processes are of high quality. These criteria include quality of goods, payment methods, payment terms, minimum transactions, discounts, delivery times, inventory, and service. The optimal weight for each criterion will be determined based on its importance to the synthesis process and its feasibility tested using mathematical algebra matrices and expert choice apps. Decision-making was based on the results of ranking evaluation of selected vendors through the development of 342 preference matrices, ten vendors were deemed worthy of acceptance and nine other vendors were rejected.
Efeitos da capacidade gerencial dos gestores sobre a condição financeira dos grandes municípios brasileiros
Authors: Sales Filho Marcos Aurelio , Lima Severino Cesário de , Vieira Luís Manuel Esteves da Rocha
Published: December 2023

Este estudo teve como objetivo verificar a influência da capacidade gerencial dos gestores na condição financeira dos grandes municípios brasileiros. Baseado no corpo teórico, foram elaboradas hipóteses de que a escolaridade e a experiência dos prefeitos, a escolaridade dos diretores de administração e finanças, e a escolaridade dos servidores públicos podem influenciar positivamente a condição financeira dos governos locais sob o aspecto orçamentário e de caixa. O estudo abrangeu os 100 maiores municípios brasileiros em termos de PIB, no período de 2009 a 2019. Para testar as hipóteses propostas utilizou-se a técnica de regressão por mínimos quadrados generalizados (GLS). Os resultados revelaram que a capacidade gerencial dos gestores e colaboradores exerce influência positiva na condição financeira dos grandes municípios brasileiros sob o aspecto da solvência de caixa, mas não é importante para influenciar a solvência orçamentária. Os resultados da pesquisa são corroborados com os pressupostos da teoria do capital humano, servindo como instrumentos de apoio à gestão das finanças públicas.
Identificação de demandas psicológicas em pacientes atendidos por interconsulta: divergências na percepção de médicos e psicólogos
Authors: Jesus Gabriel Ramalho de , Nakao Renata Tamie , Rodrigues Mateus Augusto , Marucci-Dalpicolo Flavia Andressa Farnocchi
Published: December 2023

O adoecimento e a necessidade de internação hospitalar podem implicar em prejuízo psicológico ao paciente. Neste sentido, o trabalho em equipes multiprofissionais configura-se como uma importante ferramenta para oferecer atenção integral à saúde. A interconsulta psicológica se caracteriza por um atendimento breve e focado, solicitado pela equipe responsável pelo cuidado do paciente, no qual o psicólogo propõe condutas em conjunto com a equipe de saúde. O objetivo deste estudo foi comparar as demandas psicológicas identificadas pelo médico no pedido de interconsulta, com as demandas avaliadas pelo psicólogo no primeiro atendimento a pacientes hospitalizados em um hospital universitário de nível terciário. Os dados foram obtidos no prontuário médico, categorizados pelos pesquisadores segundo o método quantitativo-interpretativo e analisados em termos de frequência e porcentagem pelo teste de McNemar e grau de concordância entre os avaliadores pelo Coeficiente de Concordância de Kappa. Cento e quatro pedidos de interconsulta realizados entre março de 2017 e março de 2018 foram avaliados, com predominância de pacientes do sexo feminino (59,8), com mais de 50 anos (63%) e profissionalmente inativos (61,9%). A maioria das solicitações teve origem na clínica médica (80,8%) e em paciente com quadro crônico (52,9%). Os resultados encontrados foram descritos em 11 categorias. Notou-se que houve maior concordância entre os cuidadores no reconhecimento de sintomas emocionais como justificativa de intervenção psicológica, o que encontrou correspondência com a literatura científica disponível. Observaram-se discordâncias na percepção de demandas entre os profissionais, especialmente sobre sofrimento emocional relacionado a dificuldades na compreensão do diagnóstico e/ou tratamento, pouco suporte familiar/social, problemas de adaptação à internação hospitalar e problemas emocionais não relacionados à doença. Conclui-se que a perspectiva multiprofissional é uma estratégia importante para promover atenção integral ao paciente,tendo a interconsulta como possibilidade efetiva, e que a abordagem do paciente apresenta diferentes perspectivas, vinculadas aos saberes de cada componente da equipe. Destaca-se a necessidade de investir na formação para a identificação e manejo de problemas de ordem emocional, comunicação e bom relacionamento médico-paciente, e observação de aspectos da história individual que possam contribuir para o bom desfecho do tratamento. Também, mostra-se importante que a formação acadêmica instrumentalize os profissionais para o trabalho em equipe multiprofissional, o que requer habilidades de comunicação, sensibilidade e compreensão sobre a complementaridade dos saberes.
Sarcoma de Kaposi, sífilis e neurocriptococose em paciente HIV positivo
Authors: Barreiro Francisca Raimunda de Souza , Nogueira Pedro Henrique Fonseca , Blasi Neto Sérgio Ítalo , Rodrigues Kassielly Melissa Ribeiro , Fabris Nathalia Bianco , Oliveira Emille Alves Itavar
Published: December 2023

A infecção pelo vírus da imunodeficiência humana (HIV) tornou-se um problema de saúde pública em todo o mundo nas últimas décadas. A principal característica do HIV é a supressão do sistema imunológico pelo ataque aos linfócitos T CD4+ que enfraquece o sistema imunológico e torna o indivíduo suscetível a infecções oportunistas,neoplasias secundárias e doenças neurológicas. Este estudo objetiva relatar e discutir o caso de um paciente HIV positivo que apresentou concomitantemente Sarcoma de Kaposi (SK), sífilis e neurocriptococose, todas doenças relacionadas ao HIV. Trata-se de um paciente masculino, 31 anos, que procurou o serviço do hospital de referência com lesões cutâneas violáceas em face, membros superiores e tórax, com três meses de evolução. Ao exame dermatológico exibiu placas eritematovioláceas infiltrativas, com bordas regulares, elevadas, descamativas e com diâmetros variáveis. Obteve sorologia positiva para anticorpos anti-HIV e VDRL, iniciando protocolos de terapiaantirretroviral (TARV) e de tratamento para sífilis. O paciente retornou ao serviço 30 dias após alta hospitalar, com queixa de cefaleia de forte intensidade, refratária à analgesia com opioides, associada a vômitos persistentes. Realizada tomografia computadorizada de crânio, sem alterações, e, posteriormente, punção liquórica que evidenciou a presença de criptococo. Iniciado esquema terapêutico para neurocriptococose e realizadas outras duas punções liquóricas para alívio do quadro álgico. Este relato está de acordo com o que presume a literatura médica, reafirmandoque pacientes HIV positivos apresentam maior predisposição para condições como o SK, a sífilis e a neurocriptococose. Dessa forma, o estudo ilustra com ineditismo a ocorrência simultânea de complexas manifestações clínicas no mesmo paciente imunossuprimido.
Satisfação de médicos e pacientes com as estratégias de telemedicina adotadas durante a pandemia de COVID-19 em um hospital pediátrico
Authors: Souza e Silva Gabriel Alcala , Carmona Fabio
Published: December 2023

Objetivo: Este estudo teve como objetivo avaliar a satisfação dos pacientes ou seus responsáveis e dos profissionaisde saúde em relação à telemedicina implantada no HC-Criança, um hospital pediátrico terciário, durante a pandemia da COVID-19. Métodos: Para cada grupo (pacientes/cuidadores e médicos) foi enviado um questionário eletrônico contendo perguntas que foram respondidas em escala de Likert sobre suas experiências com o uso da telemedicina. Resultados: Foram obtidas 81 respostas válidas de médicos e 1.721 de pacientes ou responsáveis. Entre pacientes ou cuidadores, 892 (52%) relataram não ter recebido nenhum atendimento por telemedicina. A maioria dos pacientes/cuidadores que receberam atendimento por telemedicina pelo menos uma vez relatou não ter sido treinada para usar a telemedicina (77%), enquanto a satisfação geral foi de 56%. A maioria (78%) acredita que a telemedicina pode ser adotada após a pandemia. Entre os médicos, 77% relataram não terem sido treinados para usar a telemedicina, 56% avaliaram sua experiência com a telemedicina como satisfatória, e 78% acreditam que a telemedicina pode ser adotada no futuro. Conclusão: A satisfação com a telemedicina de pacientes, seus cuidadores e profissionais de saúde do HC Criança foi boa durante a pandemia da COVID-19, mesmo sem receberem treinamento adequado, e eles acreditam que a telemedicina pode ser adotada após a pandemia.