bluuebunny/crossref_metadata_2025 huggingface dataset:
Deconvolving Clinically Relevant Cellular Immune Cross-talk from Bulk Gene Expression Using CODEFACS and LIRICS Stratifies Patients with Melanoma to Anti–PD-1 Therapy
Authors: Wang Kun , Patkar Sushant , Lee Joo Sang , Gertz E. Michael , Robinson Welles , Schischlik Fiorella , Crawford David R. , Schäffer Alejandro A. , Ruppin Eytan
Published: January 2022

The tumor microenvironment (TME) is a complex mixture of cell types whose interactions affect tumor growth and clinical outcome. To discover such interactions, we developed CODEFACS (COnfident DEconvolution For All Cell Subsets), a tool deconvolving cell type–specific gene expression in each sample from bulk expression, and LIRICS (Ligand–Receptor Interactions between Cell Subsets), a statistical framework prioritizing clinically relevant ligand–receptor interactions between cell types from the deconvolved data. We first demonstrate the superiority of CODEFACS versus the state-of-the-art deconvolution method CIBERSORTx. Second, analyzing The Cancer Genome Atlas, we uncover cell type–specific ligand–receptor interactions uniquely associated with mismatch-repair deficiency across different cancer types, providing additional insights into their enhanced sensitivity to anti–programmed cell death protein 1 (PD-1) therapy compared with other tumors with high neoantigen burden. Finally, we identify a subset of cell type–specific ligand–receptor interactions in the melanoma TME that stratify survival of patients receiving anti–PD-1 therapy better than some recently published bulk transcriptomics-based methods.

Significance:

This work presents two new computational methods that can deconvolve a large collection of bulk tumor gene expression profiles into their respective cell type–specific gene expression profiles and identify cell type–specific ligand–receptor interactions predictive of response to immune-checkpoint blockade therapy.

This article is highlighted in the In This Issue feature, p. 873
Abstract IA01: Unconventional ER stress response pro-tumorigenic polarization and survival in TAMs
Authors: Ho Ping-Chih
Published: January 2022

Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here we uncover that tumor cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP-1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, our findings reveal the unexpected roles of tumor cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and therapeutic targets for sustaining host anti-tumor immunity.

Citation Format: Ping-Chih Ho. Unconventional ER stress response pro-tumorigenic polarization and survival in TAMs [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA01.
Abstract IA07: Impact of immunotherapy on COVID-19 immunity: Insights from checkpoint blockade in cancer
Authors: Coutifaris Paulina , Wang Kevin , Apostolidis Sokratis , Painter Mark , Flowers Ahron , Goel Rishi , Mathew Divij , Pattekar Ajinkya , Amaravadi Ravi , Mitchell Tara , Bates Paul , Hensley Scott , Karakousis Giorgos , Schuchter Lynn , Greenplate Allie , Wherry E. John , Huang Alexander C.
Published: January 2022

Over the last few years, we have gained insights into how immunotherapy, including checkpoint blockade, modulates key CD4 and CD8 T cell subsets in anti-tumor immunity. This information can now give us insights into how immunotherapy can impact immunity in the setting of COVID-19. Indeed, we recently demonstrated that cancer patients with T cell depletion have high COVID-19 mortality despite adequate B cell and antibody production, highlighting the importance of cellular immunity. Conversely, in the setting of B cell depletion by anti-CD20 therapy, CD8 T cells can compensate for impaired humoral immunity. PD-1 blockade increases the activation and proliferation of CD4 T follicular-helper cells, which plays a key role in promoting B cell responses and quality antibody production. Thus, it is possible that PD-1 blockade enhances the efficacy of SARS-CoV-2 vaccination. However, PD-1 blockade in melanoma patients was actually associated with at 2-fold decrease in SARS-CoV-2 specific antibodies and neutralizing antibodies, compared to a healthy donor cohort. PD-1 blockade was also associated with depletion of memory CD4 T cells, suggesting there may be consequences to prolonged PD-1 blockade.

Citation Format: Paulina Coutifaris, Kevin Wang, Sokratis Apostolidis, Mark Painter, Ahron Flowers, Rishi Goel, Divij Mathew, Ajinkya Pattekar, Ravi Amaravadi, Tara Mitchell, Paul Bates, Scott Hensley, Giorgos Karakousis, Lynn Schuchter, Allie Greenplate, E. John Wherry, Alexander C. Huang. Impact of immunotherapy on COVID-19 immunity: Insights from checkpoint blockade in cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA07.
Abstract IA12: Cancer evolution: Chromosomal instability and immune evasion
Authors: Swanton Charles
Published: January 2022

Evidence supports complex subclonal relationships in solid tumors, manifested as intratumor heterogeneity. Parallel evolution of subclones, with distinct somatic events occurring in the same gene, signal transduction pathway or protein complex, suggests constraints to tumor evolution that might be therapeutically exploitable. Data from TRACERx, a longitudinal lung cancer evolution study will be presented. Drivers of tumor heterogeneity change during the disease course and contribute to the temporally distinct origins of lung cancer driver events. APOBEC driven mutagenesis appears to be enriched in subclones in multiple tumor types. Oncogene, tumor suppressor gene and drug-induced DNA replication stress are found to drive APOBEC mutagenesis. On-going chromosomal instability, manifested as Mirrored Subclonal Allelic Imbalance (MSAI) is found to be a major driver of intratumor heterogeneity across cancer types, contributing to parallel evolution and selection. Subclonal driver events, evidence of ongoing selection within subclones, combined with genome instability driving cell-to-cell variation is likely to limit the efficacy of targeted monotherapies, suggesting a need for new approaches to drug development and integration of cancer immunotherapeutic approaches. Multiple adaptive mechanisms to neo-antigen evolution have been found in TRACERx highlighting cancer chromosomal instability driving immune evasion and HLA loss and loss of clonal neo-antigens as well as epigenetic repression of neo-antigens. The clonal neo-antigenic architecture may act as a tumor vulnerability to mitigate resistance and treatment failure.

Citation Format: Charles Swanton. Cancer evolution: Chromosomal instability and immune evasion [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA12.
Abstract IA22: Immunotherapy for melanoma: Checkpoint blockade combinations
Authors: Wolchok Jedd D.
Published: January 2022

Given the activity noted with both CTLA-4 or PD-1 blockade, clinical trials are now investigating combination checkpoint blockade. The most mature data with a combination of ipilimumab + nivolumab in melanoma showed a response rate of 60% in the context of increased, yet manageable toxicity. Such responses are generally durable, even when treatment was stopped early for toxicity. Unlike in studies of PD-1 blockade monotherapy, there was no significant difference in clinical activity based on tumor expression of PD-L1. This approach has gained US regulatory approval for metastatic melanoma and is in late stage clinical trials for other malignancies. Attention is being paid to the reasons underlying the efficacy of checkpoint blockade in certain malignancies. One hypothesis has been that cancers having a high mutational load may be more amenable to immune modulation by virtue of the larger number of potential neo-epitopes present, fostering baseline immune recognition that can then be potentiated by checkpoint blockade. We have found that melanoma patients having long term clinical activity with ipilimumab have a significantly greater median number of non-synonymous passenger mutations, compared with patients who do not respond or those who have only short-term regression. Strategies to enhance baseline immune reactivity are therefore necessary to investigate as means to improve the impact of checkpoint blockade on a broad spectrum of cancers. The presence of suppressive myeloid cells and regulatory T cells in the tumor microenvironment is emerging as a mechanism of resistance to the anti-tumor activity for checkpoint blockade. Strategies to overcome this include agonism of GITR and selective suppression of PI3K-g.

Citation Format: Jedd D. Wolchok. Immunotherapy for melanoma: Checkpoint blockade combinations [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA22.
Abstract P051: Function of shp-1 and shp-2 phosphatases in T cell-mediated anti-tumor response
Authors: Ventura Pedro , Gakovic Milica , Fischer Berenice , Thomson Sarah , Khameneh Hanif J , Zenobi Alessandro , Rota Giorgia , Vivier Eric , Birchmeier Walter , Cantrell Doreen , Guarda Greta
Published: January 2022

After exposure to chronic inflammatory stimuli, the immune system can switch from a functional state where it acts to reestablish homeostasis to a dysfunctional state. In the context of cancer, T cells that become exposed to continuous stimulation eventually reach a state of exhaustion, characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Although PD-1 signaling inhibition leads to T cell reinvigoration and has been applied as an effective treatment versus a wide range of tumors, the signaling pathway downstream of this receptor is still poorly understood. Recent work from others and us challenged the notion that the phosphatase shp-2 is essential for activation of the molecular cascade downstream PD-1 receptor engagement. The shp-2 homologue (shp-1) has also been associated with PD-1 signaling in T cells and functional redundancy between these phosphatases might occur downstream of this receptor. Therefore, we investigated the effect of shp-1 and the combination of both (shp-1/2) downstream of PD-1 by knocking out these phosphatases in T cells in a mouse model. In vivo results after tumor engraftment suggest that shp-1 as well as shp-1/2 deletion in T cells are not sufficient to ameliorate tumor control. Furthermore, ablation of shp-1 and shp-1/2 impair the beneficial effects of the anti-PD1 treatment. In fact, deletion of both phosphatases leads to decrease CD8+ T cell presence in the tumor microenvironment and in vitro results show that these cells have impaired survival. This data implies that elimination or inhibition of shp-1/2 is not a suitable strategy for effective immunotherapeutic approaches as well as highlights the importance of further elucidating the mechanisms behind this important inhibitory pathway.

Citation Format: Pedro Ventura, Milica Gakovic, Berenice Fischer, Sarah Thomson, Hanif J Khameneh, Alessandro Zenobi, Giorgia Rota, Eric Vivier, Walter Birchmeier, Doreen Cantrell, Greta Guarda. Function of shp-1 and shp-2 phosphatases in T cell-mediated anti-tumor response [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P051.
Abstract P052: Functional ADORA2A antibodies demonstrates the antagonistic and tumor suppression activities
Authors: Wang Linya , Lujan Ana , Kwan Eric , Safavi Crystal , Villalta Mouna , Yuan Tom , Mathur Melina , Lai Joyce , Giang Hoa , Liu Qiang , Axelrod Fumiko , Sato Aaron
Published: January 2022

G protein-coupled receptors (GPCRs), a family of seven-transmembrane receptor proteins function as sensors transmitting extracellular signals into the cell and mediate a diverse range of ligand signaling, are proven to be successful drug targets. GPCRs and the associated downstream signaling pathways have been linked to a wide range of disease types such as cancer, inflammatory and immune disorders, as well as metabolic and neurological diseases. Antibodies are becoming an increasingly promising modality to target these receptors due to their unique properties, such as exquisite specificity, long half-life, and fewer side effects, and their improved pharmacokinetic and pharmacodynamic profiles compared to peptides and small molecules, which results from their more favorable biodistribution. To date, there are only two US Food and Drug Administration-approved GPCR antibody drugs, namely erenumab and mogamulizumab, and this highlights the challenges encountered in identifying functional antibodies against GPCRs. ADORA2A operates as an adenosine receptor and immune checkpoint protein that prevents the inappropriate activation of T-cells and is an immuno-oncology target. Immune checkpoint blockades are one of the newest pillars of cancer therapeutic development. Current examples for targeting ADORA2A involve small molecule antagonists. Selective antibody binders of ADORA2A are therefore a largely untapped immunotherapeutic candidate. Using our proprietary biologics discovery and optimization platform, Twist Biopharma identified a potent high-affinity antibody, TB206-001, amongst other promising leads. Initial in vitro assays showed that TB206-001 binds with high affinity to both human and mouse ADORA2A. TB206-001 showed antagonistic activity by suppressing cAMP level stimulated by NECA, a high affinity adenosine receptor agonist. Primary T cell assays demonstrated that TB206-001 restored T cell activity which was inhibited by NECA which suppresses T cell activation. Subsequent in vivo testing also showed the efficacy in animal models of cancer, indicating its activity in tumor suppression. TB206-001 is a high-affinity antagonistic anti-ADORA2A antibody demonstrating preclinical activity.

Citation Format: Linya Wang, Ana Lujan, Eric Kwan, Crystal Safavi, Mouna Villalta, Tom Yuan, Melina Mathur, Joyce Lai, Hoa Giang, Qiang Liu, Fumiko Axelrod, Aaron Sato. Functional ADORA2A antibodies demonstrates the antagonistic and tumor suppression activities [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P052.
Abstract P053: Ablation of CCR1 relieves immunosuppression in pancreatic cancer
Authors: Zhang Yaqing , Brown Kristee L. , Yan Wei , Nwosu Zeribe C. , Carpenter Eileen K. , Donahue Katelyn L. , Velez-Delgado Ashley , Yang Sion , Pasca di Magliano Marina
Published: January 2022

Pancreatic Cancer is one of the deadliest malignancies, with 5-year survival rate of 10%. The tumor microenvironment of pancreatic ductal adenocarcinoma (PDA) includes abundant fibroblasts and infiltrating immune cells, the latter largely immunosuppressive. Mono-immunotherapy or combination immunotherapy approaches has been ineffective in pancreatic cancer, pointing to the need for additional avenues to target in pancreatic cancer microenvironment. We previously showed that targeting regulatory T cell (Treg), a prevalent T cell population in pancreatic cancer, failed to relieve immunosuppression and led to accelerated tumor progression. We discovered that Treg depletion reprogrammed tumor associated fibroblasts and increased immunosuppressive myeloid cell recruitment, an effect that was partially mediated by CCLs/CCR1signaling. We found that tumor educated macrophages express the highest levels of Ccr1 compared to non-activated (M0), pro-inflammatory (M1), or anti-inflammatory (M2) bone marrow derived macrophage subsets. Thus, we sought to investigate the functional role of CCR1 in pancreatic cancer. By single cell RNA sequencing, we found CCR1 to be mainly expressed by tumor associated macrophages (TAMs) and neutrophils (or granulocytes) in both human and mouse PDA. We then orthotopically transplanted syngeneic mouse pancreatic cancer cells in CCR1 knockout hosts and observed reduced tumor growth which was rescued by CD8 T cell depletion. Histological analysis showed elevated Granzyme B expression in infiltrating T cells, as well as an increase in apoptotic cells in tumors implanted in Ccr1−/− mice. Through cytometry by time of flight (CyTOF) and co-immunofluorescence we also discovered that TAMs in tumors implanted in Ccr1−/− mice expressed less Arginase 1 and CD206 -both markers of immunosuppressive macrophages- compared to TAMs in wild type tumors. Thus, our data is consistent with the notion that tumor associated macrophages lacking CCR1 expression are less immunosuppressive, consequently allowing increased CD8 T cell-mediated anti-tumor immunity. We are currently exploring combination approaches targeting CCR1 in pancreatic cancer.

Citation Format: Yaqing Zhang, Kristee L. Brown, Wei Yan, Zeribe C. Nwosu, Eileen K. Carpenter, Katelyn L. Donahue, Ashley Velez-Delgado, Sion Yang, Marina Pasca di Magliano. Ablation of CCR1 relieves immunosuppression in pancreatic cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P053.
Abstract P054: Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types
Authors: Sinha Neelam , Sinha Sanju , Valero Christina , Schaffer Alejandro A. , Aldape Kenneth , Litchfield Kevin , Chan Timothy A. , Morris Luc G. T. , Ruppin Eytan
Published: January 2022

The FDA has recently approved a high tumor mutational burden (TMB-High, defined by ≥10 mutations/Mb) as a biomarker for the treatment of advanced solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies have shown that this TMB-high biomarker is only able to stratify ICI responders in a subset of cancer types, where the mechanisms underlying this observation have remained unknown. We hypothesized that the tumor immune microenvironment (TME) may determine the ability of high-TMB to stratify responders of ICI (termed TMB power) in each cancer type. To systematically study this hypothesis, we first inferred the levels of 31 immune-related factors characteristic of the TME of different cancer types in the TCGA. We next integrated this information with a cohort of 2,277 ICI-treated patients with TMB and response measures, to identify the key immune factors that can determine TMB power across 14 different cancer types. This cohort was created by collating the largest publicly available cohort comprising 1959 patients together with a new cohort of 318 patients, where TMB has been quantified using the MSK-IMPACT panel. We find that high levels of M1 macrophages and low levels of resting dendritic cells in the TME characterize cancer types with high TMB power. These findings are aligned with prior reports that M1 macrophages could be anti-tumorigenic by fostering an inflammation response and activating CD8 T cells against tumor, and that resting dendritic cells may induce tolerance to tumor antigens via inducing T cell death or their anergic state. A model based on these two immune factors strongly predicts TMB power across cancer types (Spearman Rho=0.76, P<3.6E-04). Using this model, we provide predictions of the TMB power in nine additional cancer types, including rare cancers, for which TMB and ICI response data are not yet publicly available on a large scale. These predictions can be used to prioritize the clinical trials testing the usage of TMB-high biomarker in new cancer types. In this line, our analysis indicates that TMB-High may be strongly predictive of ICI response in cervical squamous cell carcinoma, suggesting that such a study should be prioritized.

Citation Format: Neelam Sinha, Sanju Sinha, Christina Valero, Alejandro A. Schaffer, Kenneth Aldape, Kevin Litchfield, Timothy A. Chan, Luc G. T. Morris, Eytan Ruppin. Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P054.
Abstract P055: Evaluation of an immunoPET tracer for IL-12 in a preclinical model of inflammatory immune responses
Authors: Glassbrook James E. , Mandella Joshua , Viola-Villegas Nerissa T. , Gibson Heather M.
Published: January 2022

IL-12 is an attractive target for imaging active antitumor immunity, inflammation, and infection due to its function in innate and adaptive immune signaling. It has been widely reported to be involved in cancer initiation and progression, autoimmunity, as well as graft vs host disease. Here, we report the development and preclinical evaluation of an IL-12-specific positron emission tomography (PET) tracer. Biodistribution of tracer was evaluated in BALB/c mice, using lipopolysaccharide (LPS) administered intramuscularly to mimic infection and stimulate IL-12 production (40µg LPS in 50µL PBS). One hour post administration each participant received intraveinous administration of [89Zr]- αIL12 tracer, and PET images were taken 5, 24, 48, and 72 hours post injection (hpi). Representative planar images show significantly higher uptake in LPS-treated mice as compared to controls. In a separate cohort of LPS-treated BALB/c mice, all tissues identified as significantly different via tracer were collected and evaluated via qPCR to verify IL-12 transcription in each tissue. To evaluate the utility of [89Zr]- αIL12 as a metric of cancer immunotherapy response where antigen presenting cells are activated, we tested intratumoral delivery of Adv/GM-CSF, which we has been shown to promote anti-tumor immunity. BALB/c mice were seeded orthotopically with TUBO (murine mammary carcinoma) in the mammary fat pad. Once TUBO tumors reached a volume of ~50 mm3, mice were divided into treated and untreated groups. Treated mice received three intratumoral injections of 108 PFU Adv/GM-CSF, once every two days, while control mice received vehicle control. On the day of the last dose, each subject received tracer injection and 72 hours later all mice were imaged via PET. Representative planar images demonstrate high uptake of [89Zr]- αIL12 in treated vs. untreated mice. Targeting of soluble cytokines such as IL-12 by PET imaging may serve as a noninvasive way to evaluate the function of the immune milieu in situ.

Citation Format: James E. Glassbrook, Joshua Mandella, Nerissa T. Viola-Villegas, Heather M. Gibson. Evaluation of an immunoPET tracer for IL-12 in a preclinical model of inflammatory immune responses [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P055.
Abstract P056: Rapid serial immunoprofiling of the tumor immune microenvironment by fine needle sampling
Authors: Oh Juhyun , Carlson Jonathan C. T. , Landeros Christian , Lee Hakho , Ferguson Scott , Faquin William C. , Clark John R. , Pittet Mikael J. , Pai Sara I. , Weissleder Ralph
Published: January 2022

As the field of cancer immunotherapy brings forth novel and combinatorial agents, there is increasing effort to discover and integrate predictive and/or prognostic biomarkers into treatment algorithms in order to optimize cancer care. While tissue-based methods can elucidate tumor-immune cell compositions at a single time point, serial assessment of the tumor immune microenvironment (TME) can provide unique insight into how various therapies may modulate target tumor and/or immune cell populations over time. We propose that single-cell sampling via fine needle aspirates (FNA) can facilitate such analyses with a favorable risk-benefit profile. Thus, we developed and optimized a multiplexed bioorthogonal approach (FAST-FNA) which has been coupled with a deep learning algorithm that allows for comprehensive cellular analyses of FNA samples. We demonstrate that the FAST-FNA assay reproducibly captures the TME profile as compared to standard labor-intensive flow cytometry and immunohistochemical assays, and, furthermore, allows for time course analysis of the evolving TME in mouse and human cancers in vivo. The translational significance of the FNA-based technology is highlighted in the ability to rapidly assess PD-L1 expression within the TME and is further extended through the serial quantitation of both tumor and immune cell markers in cancer patients treated with immunotherapy. Collectively, these data indicate that FAST-FNA can serve as a robust and versatile clinical tool to monitor the evolving TME and has the potential to provide early insight into treatment response.

Citation Format: Juhyun Oh, Jonathan C. T. Carlson, Christian Landeros, Hakho Lee, Scott Ferguson, William C. Faquin, John R. Clark, Mikael J. Pittet, Sara I. Pai, Ralph Weissleder. Rapid serial immunoprofiling of the tumor immune microenvironment by fine needle sampling [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P056.
Abstract P058: Tumor-targeted IL-2 by engineered mesenchymal stem cells reinvigorates CD8+ T cells
Authors: Bae Joonbeom , Liu Longchao , Timmerman Casey , Hsu Eric , Zhang Anli , Zhu Jiankun , Fu Yang-Xin
Published: January 2022

Tumor microenvironment (TME) generates immunosuppressive niche to induce CD8+ tumor infiltrating lymphocytes (TILs) exhaustion. Therapeutic targeting to functionally reinvigorate CD8+ T cells is a promising strategy to enhance antitumor immunity. While interleukin-2 (IL-2) based therapies cause potent T cell activation and proliferation, the clinical application remains challenging due to short half-life and severe toxicity at therapeutic doses. To address this, we engineered mesenchymal stem cells (MSCs) to successfully proliferate and turn on or off CD8 T cell-preferential IL-2 mutein/Fc fusion protein (SIL2-EMSC) to target cytotoxic T cells in the TME. Peritumoral administration of SIL2-EMSCs permits local production of sufficient SIL2 inside the TME and induces complete tumor regression without adverse toxicity. Mechanistically, SIL2-EMSC remodels the TME that activates and expands preexisting CD8+ TILs. Furthermore, local treatment of SIL2-EMSC elicits systemic antitumor responses for the clearance of distal tumor and metastasis. In advanced tumors, SIL2-EMSCs can overcome resistance to immune check blockade (ICB) and β-lapachone (β-lap) chemotherapy. The therapeutic benefits of SIL2-EMSC were also observed in humanized mouse models. Overall, tumor-targeted delivery of cytokines by next generation of MSCs reverses immunosuppressive environment, improves antitumor effects, and synergize with various therapies without adverse toxicity.

Citation Format: Joonbeom Bae, Longchao Liu, Casey Timmerman, Eric Hsu, Anli Zhang, Jiankun Zhu, Yang-Xin Fu. Tumor-targeted IL-2 by engineered mesenchymal stem cells reinvigorates CD8+ T cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P058.
Abstract P076: Humanized anti-αvβ3 antibody engineered to selectively promote macrophage-mediated cancer cell death
Authors: Wettersten Hiromi I. , Shepard Ryan M. , Weis Sara M. , Cheresh David A.
Published: January 2022

Integrin αvβ3, an epithelial-to-mesenchymal transition marker, promotes drug resistance and metastasis in a range of epithelial cancers. Hence, a humanized anti-αvβ3 antibody (Etaracizumab), developed in the 1990s, was designed to eliminate αvβ3+ cells via NK-mediated antibody-dependent cellular-cytotoxicity (ADCC). Etaracizumab has been tested in clinical trials and proven to be safe with some activity in a subset of patients. However, in a recent examination of the immune microenvironment of αvβ3+ human epithelial tumors, we observed a large number of tumor-associated macrophages (TAMs) but minimal accumulation of NK or T cells. This suggests the efficacy of Etaracizumab may have been limited based on the relative lack of NK cells in αvβ3+ tumors. Therefore, we re-engineered Etaracizumab by changing its Fc receptor binding properties to favor TAM engagement over NK cells. This newly designed anti-αvβ3 antibody (ABT-101) while binding to αvβ3 with the same affinity as Etaracizumab, not only eliminates tumor cells via TAM-mediated ADCC but promotes a two-fold increased anti-tumor activity in mice and accumulates to a higher degree in tumors compared to Etaracizumab. Based on these preclinical findings, ABT101 is currently being evaluated in IND enabling studies with the hope to initiate phase I clinical trials in mid-2022.

Citation Format: Hiromi I. Wettersten, Ryan M. Shepard, Sara M. Weis, David A. Cheresh. Humanized anti-αvβ3 antibody engineered to selectively promote macrophage-mediated cancer cell death [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P076.
Abstract P078: Synergistic immunotherapy effects of anti-COVID-19 and anti-cancer vaccines in preventing tumors and infections
Authors: Garimella Narayana
Published: January 2022

To assure efficacy, safety and security of medicines and products including those of cancer and infection prevention ones, the concepts of immunology and immunotherapy, treatments, therapeutics, research, reviews, approvals and according agency, nation and world-wide managements are highly important. Often rationally planned combinations of U.S. Food and Drug Administration (USFDA) approved medicines in preventing or treating the same or similar or multiple diseases are realized to be pharmacologically and biologically effective in mechanisms and toxicologically safe in applications. Because, multiple mechanisms are simultaneously combined in enhancing systemic immunities within the permissible limits of the doses. In this work, the immunology and immunotherapy aspects of both anti-cancer vaccines and anti-COVID-19 vaccines are taken into account to prevent current and future occurrences of cancer and infectious diseases. Though the intended mechanisms of actions are only disease specific and are primarily different between anti-cancer and anti-COVID-19 vaccines, their combinations are worthwhile in providing synergistic effects against carcinogenesis, metastasis and infections. Based on the chemical, biological and pharmacological input and output information for both kinetics and dynamics of vaccines including mRNA-1273, BNT162b2, and JNJ-78436735 to prevent covid-19 are explored in combinations with anti-cancer vaccines including Human Papillomavirus (HPV) Vaccine and Hepatitis B Vaccine (HBV). In addition to safety and efficacy, mRNA, viral-vector, protein and antigen mechanisms, pH, vaccine-vaccine interactions, independent and combined dose regimens, toxicities, solubilities, intrinsic and extrinsic covariates were taken into account for careful planning of combinations. Simultaneous dual combinations from both groups were improved to three to five levels of combinations. It was realized that these combinations qualify for pre-clinical followed by clinical-investigations further. Also, these conclusions promised us to explore additional new and approved vaccines of these indications.

Citation Format: Narayana Garimella. Synergistic immunotherapy effects of anti-COVID-19 and anti-cancer vaccines in preventing tumors and infections [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P078.
Abstract PR09: Macrophage promotion of anti-androgen resistance in prostate cancer bone disease
Authors: Li Xue-Feng , Selli Cigdem , Unciti-Broceta Asier , Carragher Neil O. , Hu Hai-Yan , Sawyers Charles L. , Qian Bin-Zhi
Published: January 2022

Metastatic castration resistant prostate cancer (mCRPC) is the final stage of prostate cancer (PC) that acquires resistance to androgen deprivation therapies (ADT). Despite many recent progresses in the mechanistic understanding of ADT resistance, the specific contribution of the metastatic microenvironment in mCRPC remains largely unknown. A novel in vivo model of androgen dependent bone metastatic PC was developed in address this question. Our identified that macrophages are the major stromal cells in bone metastatic PC. Using multiple genetic models, we demonstrated that macrophages, both monocyte-derived and bone resident populations, were critical for bone metastatic PC to develop resistance to enzalutamide, a clinically used anti-androgen. Mechanistically, macrophages drove resistance through induction of a wound healing like response in prostate cancer cells, which was strongly supported by bioinformatics analysis of multiple patient mCRPC datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth of mCRPC. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease.

Citation Format: Xue-Feng Li, Cigdem Selli, Asier Unciti-Broceta, Neil O. Carragher, Hai-Yan Hu, Charles L. Sawyers, Bin-Zhi Qian. Macrophage promotion of anti-androgen resistance in prostate cancer bone disease [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr PR09.
Integrated energy management converter based on maximum power point tracking for photovoltaic solar system
Authors: Ouremchi Mounir , El Mouzouade Said , El Khadiri Karim , Tahiri Ahmed , Qjidaa Hassan
Published: January 2022

This paper presents an integrated power control system for photovoltaic systems based on maximum power point tracking (MPPT). The architecture presented in this paper is designed to extract more power from photovoltaic panels under different partial obscuring conditions. To control the MPPT block, the integrated system used the ripple correlation control algorithm (RCC), as well as a high-efficiency synchronous direct current (DC-DC) boost power converter. Using 180 nm complementary metal-oxide-semiconductor (CMOS) technology, the proposed MPPT was designed, simulated, and layout in virtuoso cadence. The system is attached to a two-cell in series that generates a 5.2 V average output voltage, 656.6 mA average output current, and power efficiency of 95%. The final design occupies only 1.68 mm2.
The voltage-mode first order universal filter using single voltage differencing differential input buffered amplifier with electronic controllability
Authors: Duangmalai Danupat , Suwanjan Peerawut
Published: January 2022

In this research contribution, the electronically tunable first-order universal filter employing a single voltage differencing differential input buffered amplifier (VD-DIBA) (constructed from two commercially available integrated circuit (IC): the operational transconductance amplifier, IC number LT1228, and the differential voltage input buffer, IC number AD830), one capacitor and two resistors. The features of the designed first order universal filter are as follows. Three voltage-mode first-order functions, low-pass (LP), all-pass (AP) and high-pass (HP) responses are given. The natural frequency (𝜔0) of the presented configuration can be electronically adjusted by setting the DC bias current. Moreover, the voltage gain of the LP and HP filters can be controllable. The phase responses of an AP configuration can be varied from 00 to −1800 and 1800 to 00. The power supply voltages were set at ±5 𝑉. Verification of the theoretically described performances of the introduced electronically tunable universal filter was proved by the PSpice simulation and experiment.
Data prediction for cases of incorrect data in multi-node electrocardiogram monitoring
Authors: Hadiyoso Sugondo , Nugroho Heru , Erawati Rajab Tati Latifah , Surendro Kridanto
Published: January 2022

The development of a mesh topology in multi-node electrocardiogram (ECG) monitoring based on the ZigBee protocol still has limitations. When more than one active ECG node sends a data stream, there will be incorrect data or damage due to a failure of synchronization. The incorrect data will affect signal interpretation. Therefore, a mechanism is needed to correct or predict the damaged data. In this study, the method of expectation-maximization (EM) and regression imputation (RI) was proposed to overcome these problems. Real data from previous studies are the main modalities used in this study. The ECG signal data that has been predicted is then compared with the actual ECG data stored in the main controller memory. Root mean square error (RMSE) is calculated to measure system performance. The simulation was performed on 13 ECG waves, each of them has 1000 samples. The simulation results show that the EM method has a lower predictive error value than the RI method. The average RMSE for the EM and RI methods is 4.77 and 6.63, respectively. The proposed method is expected to be used in the case of multi-node ECG monitoring, especially in the ZigBee application to minimize errors.
Bandwidth density optimization of misaligned optical interconnects
Authors: Aldiabat Hasan , Al-ababneh Nedal
Published: January 2022

In this paper, the bandwidth density of misaligned free space optical interconnects (FSOIs) system with and without coding under a fixed bit error rate is considered. In particular, we study the effect of using error correction codes of various codeword lengths on the bandwidth density and misalignment tolerance of the FSOIs system in the presence of higher order modes. Moreover, the paper demonstrates the use of the fill factor of the detector array as a design parameter to optimize the bandwidth density of the communication. The numerical results demonstrate that the bandwidth density improves significantly with coding and the improvement is highly dependent on the used codeword length and code rate. In addition, the results clearly show the optimum fill factor values that achieve the maximum bandwidth density and misalignment tolerance of the system.
Automatic target detection and localization using ultra-wideband radar
Authors: Daghouj Dounia , Abdellaoui Marwa , Fattah Mohammed , Mazer Said , Balboul Youness , El Bekkali Moulhime
Published: January 2022

The pulse ultra-wide band (UWB) radar consists of switching of energy of very short duration in an ultra-broadband emission chain, and the UWB signal emitted is an ultrashort pulse, of the order of nanoseconds, without a carrier. These systems can indicate the presence and distances of a distant object, call a target, and determine its size, shape, speed, and trajectory. In this paper, we present a UWB radar system allowing the detection of the presence of a target and its localization in a road environment based on the principle of correlation of the reflected signal with the reference and the determination of its correlation peak.
Symmetric quadratic tetration interpolation using forward and backward operation combination
Authors: Charnsamorn Chapkit , Khetkeeree Suphongsa
Published: January 2022

The existed interpolation method, based on the second-order tetration polynomial, has the asymmetric property. The interpolation results, for each considering region, give individual characteristics. Although the interpolation performance has been better than the conventional methods, the symmetric property for signal interpolation is also necessary. In this paper, we propose the symmetric interpolation formulas derived from the second-order tetration polynomial. The combination of the forward and backward operations was employed to construct two types of the symmetric interpolation. Several resolutions of the fundamental signals were used to evaluate the signal reconstruction performance. The results show that the proposed interpolations can be used to reconstruct the fundamental signal and its peak signal to noise ratio (PSNR) is superior to the conventional interpolation methods, except the cubic spline interpolation for the sine wave signal. However, the visual results show that it has a small difference. Moreover, our proposed interpolations converge to the steady-state faster than the cubic spline interpolation. In addition, the option number increasing will reinforce their sensitivity.
Binary classification of rainfall time-series using machine learning algorithms
Authors: Hudnurkar Shilpa , Rayavarapu Neela
Published: January 2022

Summer monsoon rainfall contributes more than 75% of the annual rainfall in India. For the state of Maharashtra, India, this is more than 80% for almost all regions of the state. The high variability of rainfall during this period necessitates the classification of rainy and non-rainy days. While there are various approaches to rainfall classification, this paper proposes rainfall classification based on weather variables. This paper explores the use of support vector machine (SVM) and artificial neural network (ANN) algorithms for the binary classification of summer monsoon rainfall using common weather variables such as relative humidity, temperature, pressure. The daily data, for the summer monsoon months, for nineteen years, was collected for the Shivajinagar station of Pune in the state of Maharashtra, India. Classification accuracy of 82.1 and 82.8%, respectively, was achieved with SVM and ANN algorithms, for an imbalanced dataset. While performance parameters such as misclassification rate, F1 score indicate that better results were achieved with ANN, model parameter selection for SVM was less involved than ANN. Domain adaptation technique was used for rainfall classification at the other two stations of Maharashtra with the network trained for the Shivajinagar station. Satisfactory results for these two stations were obtained only after changing the training method for SVM and ANN.
Deep convolutional neural network-based system for fish classification
Authors: AL Smadi Ahmad , Mehmood Atif , Abugabah Ahed , Almekhlaﬁ Eiad , Al-smadi Ahmad Mohammad
Published: January 2022

In computer vision, image classification is one of the potential image processing tasks. Nowadays, fish classification is a wide considered issue within the areas of machine learning and image segmentation. Moreover, it has been extended to a variety of domains, such as marketing strategies. This paper presents an effective fish classification method based on convolutional neural networks (CNNs). The experiments were conducted on the new dataset of Bangladesh’s indigenous fish species with three kinds of splitting: 80-20%, 75-25%, and 70-30%. We provide a comprehensive comparison of several popular optimizers of CNN. In total, we perform a comparative analysis of 5 different state-of-the-art gradient descent-based optimizers, namely adaptive delta (AdaDelta), stochastic gradient descent (SGD), adaptive momentum (Adam), adaptive max pooling (Adamax), Root mean square propagation (Rmsprop), for CNN. Overall, the obtained experimental results show that Rmsprop, Adam, Adamax performed well compared to the other optimization techniques used, while AdaDelta and SGD performed the worst. Furthermore, the experimental results demonstrated that Adam optimizer attained the best results in performance measures for 70-30% and 80-20% splitting experiments, while the Rmsprop optimizer attained the best results in terms of performance measures of 70-25% splitting experiments. Finally, the proposed model is then compared with state-of-the-art deep CNNs models. Therefore, the proposed model attained the best accuracy of 98.46% in enhancing the CNN ability in classification, among others.
An analysis between exact and approximate algorithms for the k-center problem in graphs
Authors: Kralev Velin , Kraleva Radoslava , Ankov Viktor , Chakalov Dimitar
Published: January 2022

This research focuses on the k-center problem and its applications. Different methods for solving this problem are analyzed. The implementations of an exact algorithm and of an approximate algorithm are presented. The source code and the computation complexity of these algorithms are presented and analyzed. The multitasking mode of the operating system is taken into account considering the execution time of the algorithms. The results show that the approximate algorithm finds solutions that are not worse than two times optimal. In some case these solutions are very close to the optimal solutions, but this is true only for graphs with a smaller number of nodes. As the number of nodes in the graph increases (respectively the number of edges increases), the approximate solutions deviate from the optimal ones, but remain acceptable. These results give reason to conclude that for graphs with a small number of nodes the approximate algorithm finds comparable solutions with those founds by the exact algorithm.
A unified ontology-based data integration approach for the internet of things
Authors: Swar Ahmed , Khoriba Ghada , Belal Mohamed
Published: January 2022

Data integration enables combining data from various data sources in a standard format. Internet of things (IoT) applications use ontology approaches to provide a machine-understandable conceptualization of a domain. We propose a unified ontology schema approach to solve all IoT integration problems at once. The data unification layer maps data from different formats to data patterns based on the unified ontology model. This paper proposes a middleware consisting of an ontology-based approach that collects data from different devices. IoT middleware requires an additional semantic layer for cloud-based IoT platforms to build a schema for data generated from diverse sources. We tested the proposed model on real data consisting of approximately 160,000 readings from various sources in different formats like CSV, JSON, raw data, and XML. The data were collected through the file transfer protocol (FTP) and generated 960,000 resource description framework (RDF) triples. We evaluated the proposed approach by running different queries on different machines on SPARQL protocol and RDF query language (SPARQL) endpoints to check query processing time, validation of integration, and performance of the unified ontology model. The average response time for query execution on generated RDF triples on the three servers were approximately 0.144 seconds, 0.070 seconds, 0.062 seconds, respectively.