bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA01: Unconventional ER stress response pro-tumorigenic polarization and survival in TAMs
Authors: Ho Ping-Chih 
Published: January 2022

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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&lt;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

Abstract
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.