bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO018: Restoring the tumor-suppressed immune response during chemotherapy by targeting Mer:PTP1b interactions
Authors: Prieto-Dominguez Nestor , Ubil Eric S. 
Published: February 2021

Abstract
The development of adaptive immune checkpoint inhibitors, which prevent tumor-mediated inactivation of lymphocytes, has drastically improved outcomes for advanced cancer patients. However, only 20-30% of patients benefit from these treatments and those that do often present moderate toxicity and/or later relapse. After discovering a novel innate immune checkpoint, we have identified a therapeutic strategy to restore the tumor-suppressed immune response during chemotherapy. Here, we show that multiple tumor types (including melanoma, lung, breast and pancreatic cancers) co-cultured with murine primary macrophages suppress the expression of the essential Toll-like Receptor (TLR) signal-transducing adapter protein MyD88 by 57-81% +/- 2-5% (mean +/- SEM). In the absence of MyD88, macrophages are unable to respond to TLR stimulating Damage Associated Molecular Patterns (DAMPs) released by dying tumor cells after chemotherapy, leading to as much as 97% +/- 6% reduction in pro-inflammatory gene expression in our co-culture models. Tumors exert this suppression by activating the macrophage Mer receptor, inducing recruitment of a phosphatase, known as PTP1b, and Stat1 to Mer. Increasing association between PTP1b and Stat1 leads to reduced Stat1 phosphorylation and translocation to the nucleus as well as a downstream reduction in MyD88 expression. Treatment with a pharmacological inhibitor of PTP1b (BVT948) blocks the association of Mer, PTP1b and Stat1, restoring MyD88 expression and responsiveness to chemotherapy-released DAMPs. In chemotherapy-resistant murine syngeneic melanoma models, including B16F10 and GEMM6 (Braf V600E, Pten-/-), we show that combination therapy with BVT948 and Cisplatin or Vemurafenib, respectively, leads to a 47% reduction in tumor growth rates. Treating chemo- and immuno-therapy resistant Lewis Lung Cancer (LLC) tumor-bearing mice with combination BVT948/Cisplatin therapy leads to a similar reduction in tumor growth that is magnified with the addition of adaptive immune checkpoint blockade. In summary, we have described a novel mechanism of cancer-mediated immune suppression that dramatically reduces the immune response during chemotherapy. PTP1b inhibition could represent a novel therapeutic strategy to improve the effectiveness of conventional chemotherapy in patients with advanced malignancies.
Citation Format: Nestor Prieto-Dominguez, Eric S. Ubil. Restoring the tumor-suppressed immune response during chemotherapy by targeting Mer:PTP1b interactions [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO018.
Abstract PO023: Immune-mediated tumor growth inhibition by selective HDAC6 inhibitor SP-2-225
Authors: Grindrod Scott , Noonepalle Satish , Aghdam Nima , Velena Alfredo , Gracia-Hernandez Maria , Zevallos-Delgado Christian , Jung Mira , Dritschilo Anatoly , Villagra Alejandro 
Published: February 2021

Abstract
In addition to their canonical role in transcriptional regulation, Histone deacetylases (HDACs) regulate other cellular functions by maintaining a balance of lysine acetylation on key cellular proteins. HDAC inhibitors are under development for use in treating cancers, neurological, and immunological diseases. A barrier to the development of HDAC inhibitors has been the toxicity associated with non-selective pan-HDAC inhibitors, which simultaneously inhibit multiple HDAC isoforms. Isoform selective HDAC inhibitors offer disease targeting with an improved toxicity profile. HDAC6 presents an important target due to its role in immune regulatory processes involved in antitumor immune responses. We have shown that selective inhibition of HDAC6 regulates macrophages to recognize, phagocyte, and present antigens to the adaptive immune system. Treatment with our selective HDAC6 inhibitor, SP-2-225, was shown to enhance the production of cancer-associated antigens and macrophage antigen cross-presentation to T cells. Through a non-cytotoxic mechanism, SP-2-225 significantly reduced the tumor volume in a syngeneic SM1 melanoma model. Analysis of the tumors from treated animals showed a significant shift in the M1/M2 ratio of the infiltrating macrophages as compared to control, indicating that SP-2-225 caused a pro-inflammatory, antitumor shift in the macrophage equilibrium surrounding the tumor. This was identified as the putative mechanism through adoptive cell therapy where macrophages from naive animals were harvested and treated ex-vivo with SP-2-225. Reimplantation of these SP-2-225 ex-vivo treated macrophages resulted in reduced tumor volumes when compared to both vehicle and untreated macrophage animal cohorts. We propose that this selective inhibitor of HDAC6 offers potential as a stand-alone cancer therapy and in combination with other immunotherapies and radiation treatments.
Citation Format: Scott Grindrod, Satish Noonepalle, Nima Aghdam, Alfredo Velena, Maria Gracia-Hernandez, Christian Zevallos-Delgado, Mira Jung, Anatoly Dritschilo, Alejandro Villagra. Immune-mediated tumor growth inhibition by selective HDAC6 inhibitor SP-2-225 [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO023.
Abstract PO033: Exposure to E-cigarette aerosol reduces the expression of Toll-like receptor 3 in lung epithelial cells
Authors: Brobst Daniel , Manyanga Jimmy , Georgescu Constantin , Wren Jonathan , Queimado Lurdes 
Published: February 2021

Abstract
Background and Aim: The use of conventional cigarettes is a major and preventable health problem and the leading cause of preventable morbidity and mortality. Electronic cigarettes have been shown to yield plasma nicotine levels similar to that seen in traditional cigarette users. E-cigarettes have been touted as a healthier alternative to traditional cigarettes and as a smoking cessation tool with mixed results. The increasing use of e-cigarettes by youth is concerning with 27.5% of high school students and 10.5% of middle school students reporting using e-cigarettes in 2019. Use among young adults (18-24) is increasing with 7.6% reporting use in 2018. Toll-like receptors (TLRs) are key sensors in the activation of innate immunity. In addition to activating antiviral and pro-inflammatory responses, TLR3 in particular has been shown to behave as a death receptor, causing apoptosis in cancer cells. TLR3 expression is reduced in the airway epithelial cells of smokers, leading to a reduction in the downstream expression of type I interferons following viral infection.
Methods: E-cigarette aerosol extracts were prepared from two brands of e-cigarettes, as previously described. Mainstream tobacco smoke extract was used as a positive control. Normal lung epithelial cells were exposed for 2 weeks to e-cigarette aerosol extracts at nicotine doses comparable to those observed in e-cigarette users. Whole-cell RNA was isolated. Gene expression was assessed by RNA-sequencing and validated by western blot.
Results: Exposure of lung epithelial cells to e-cigarette aerosol extracts significantly decreased the mRNA expression levels of TLR3 (p&lt;0.0001). A significant reduction (p&lt;0.0001) in the mRNA expression of downstream innate immune system molecules including RIG1, IRF7 and interferons was also observed. The reduction in gene expression was similar to that observed from traditional cigarette smoke extracts.
Conclusions: Our study suggests that exposure to e-cigarette aerosol can decrease the expression of key genes involved in innate immune response. TLR3 expression has been associated with good prognosis in early stage lung cancer. A decrease in TLR3 expression could allow tumors to evade immune surveillance and apoptosis
Citation Format: Daniel Brobst, Jimmy Manyanga, Constantin Georgescu, Jonathan Wren, Lurdes Queimado. Exposure to E-cigarette aerosol reduces the expression of Toll-like receptor 3 in lung epithelial cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO033.
Abstract PO051: Enhancing NK cell penetration of the tumor stroma using gene modification and nanomedicine
Authors: Bonan Nicole F. , Yvon Eric , Fernandes Rohan 
Published: February 2021

Abstract
Adoptive cell therapy has shown great success in treating liquid tumors. While T cells have been most commonly used for these indications, NK cells are emerging as a promising immune effector cell against solid tumors. Solid tumors present a more heterogeneous population of tumor antigens than liquid tumors, and NK cells, unlike T cells, can target multiple antigens to decrease the likelihood of antigen escape. NK cells can also be transplanted allogeneically with a lower risk of inducing graft-versus-host disease than T cells, which makes off-the-shelf NK cell therapy both simpler than T cell therapy and available to leukopenic patients. However, barriers to treating solid tumors with adoptive cell therapy remain, including the physical barrier of the dense stroma, which blocks immune cell infiltration. This project aims to develop an adoptive cell therapy to overcome this barrier. We tested the ability of cord blood-derived NK cells to kill mesothelioma tumor cell lines H226 and H2452 in the presence of heparanase, a heparan sulfate proteoglycan endoglucuronidase that both degrades the tumor stroma and stimulates NK cell invasion. We also conjugated this heparanase to FDA-approved Prussian blue nanoparticles to determine whether these nanoparticles might increase heparanase accumulation in the tumor and protect it from degradation. We used cytotoxicity assays, transwell invasion assays, and spheroid coculture assays to determine whether heparanase or hep-PBNPs aid NK cell cytotoxicity, invasion, and penetration. Surprisingly, our results indicate that PBNPs themselves may have heparanase activity. However, our invasion and penetration assays must be repeated to fully elucidate the effect of PBNPs and hep-PBNPs on NK cell invasion.
Citation Format: Nicole F. Bonan, Eric Yvon, Rohan Fernandes. Enhancing NK cell penetration of the tumor stroma using gene modification and nanomedicine [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO051.
Abstract PO061: Prognostic significance of S100A2 expression in patients with resected lung adenocarcinoma
Authors: Hung Jung-Jyh 
Published: February 2021

Abstract
Background: Lung cancer is the leading cause of cancer death worldwide. The S100 protein family has been reported to regulate inflammatory responses, cell cycle progression, differentiation, and play an important role in initiation and progression of a variety of human cancers. Overexpression of S100A2 has been reported in a variety of cancer types. S100A2 has been reported to be a putative tumor suppressor in the early stages of carcinogenesis in lung cancer. However, other reports showed that S100A2 overexpression was significantly associated with poor survival and increased metastasis in patients with resected lung cancer. Due to the discrepancies in the direction of prognosis in the literature, the prognostic value of S100A2 in lung cancer needs further demonstration.
Methods: The clinicopathological characteristics of 85 patients with lung adenocarcinoma at Taipei Veterans General Hospital were retrospectively reviewed. Expression of S100A2 was investigated using immunohistochemistry. Their prognostic significance in probability of overall survival and disease-free survival was analyzed.
Results: With a median follow-up time of 26.7 months (26.8 ± 6.3), the 2-year probability of overall survival rate was 94.7%. By immunohistochemistry, overexpression of S100A2 was identified in 17 (20.0%) of the 85 patients. S100A2 overexpression was not a significant prognostic factor for overall survival (P = 0.122). For disease-free survival, patients with stage I disease have significantly better disease-free survival than those with stage II or III disease (P &lt; 0.001) in univariate analysis. Patients with S100A2 overexpression have a significantly worse disease-free survival (P = 0.028). In multivariate analysis, S100A2 overexpression was still a significant prognostic factor for worse disease-free survival (P = 0.019). Stage I disease was also a significant prognostic factor for better disease-free survival (P = 0.006).
Conclusions: Our study showed that S100A2 overexpression was a significant prognostic factor for worse disease-free survival in patients with resected lung adenocarcinoma.
Citation Format: Jung-Jyh Hung. Prognostic significance of S100A2 expression in patients with resected lung adenocarcinoma [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO061.
Abstract PO065: Single cell transcriptomics of triple negative breast cancer allografts following chemotherapy treatment reveals increased T cell abundance in doxorubicin-sensitive tumors
Authors: Hum Nicholas R. , Sebastian Aimy , Gilmore Sean F. , Gravano David M. , Rios-Arce Naiomy D. , Martin Kelly A. , Wheeler Elizabeth K. , Coleman Matthew A. , Loots Gabriela G. 
Published: February 2021

Abstract
The contribution of stromal cells on drug response in primary tumors remains unclear. To determine how individual cells within the stroma of triple negative breast cancer (TNBC) allografts respond to chemotherapy, we used single cell sequencing to profile cells present in murine tumors with or without exposure to doxorubicin. Doxorubicin is a chemotherapeutic agent commonly used to treat TNBC by inhibiting cancer cell proliferation through intercalation of DNA and preventing topoisomerase II activity. In this study, murine TNBC 4T1 cell line was utilized to generate allograft tumors in immunocompetent BALB/c mice. Syngeneic 4T1 tumors exhibit a range of responsiveness to doxorubicin treatment. Tumor growth rates were monitored throughout the chemotherapeutic regiment then stratified into sensitive or resistant response. Cellular composition and behavior were then analyzed via single cell RNA sequencing (scRNA-seq) and flow cytometry 8 days post-doxorubicin chemotherapeutic administration mimicking clinical treatment. ScRNA-seq revealed decreases in tumor infiltrating lymphocytes after doxorubicin exposure. Furthermore, an increase in T cell abundance was discovered in tumors sensitive to doxorubicin treatment. This finding was further supported by flow cytometric analysis showing a tumor specific increase in all, CD4+, and CD8+ T cell populations relative to resistant tumors. Additionally, T-cell differentiation, exhaustion, and activation states were further examined from scRNA-seq data providing insights into functional properties of the tumor residing T cell populations undergoing chemotherapeutic treatment. Future work will focus on analyzing prognostic value of specific T-cell populations in disease regression following doxorubicin treatment. This study received funding from LLNL LDRD grant 19-SI-003. This work was conducted under the auspices of the USDOE by LLNL (DE-AC52-07NA27344).
Citation Format: Nicholas R. Hum, Aimy Sebastian, Sean F. Gilmore, David M. Gravano, Naiomy D. Rios-Arce, Kelly A. Martin, Elizabeth K. Wheeler, Matthew A. Coleman, Gabriela G. Loots. Single cell transcriptomics of triple negative breast cancer allografts following chemotherapy treatment reveals increased T cell abundance in doxorubicin-sensitive tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO065.
Abstract PO082: Significance of Treg cells in pathogenesis of oral squamous cell carcinoma
Authors: Aggarwal Sadhna , Sharma Suresh C. , Das Satya N. 
Published: February 2021

Abstract
Oral squamous cell carcinoma (OSCC) is one of the major cancers affecting in Asian countries. The main causative factor has been tobacco habit. It has been reported that immune dysfunction in these patients is one of the major factors for tumor growth and dissemination that affects disease free survival of the patients. We assessed the phenotypic and functional characteristics of Regulatory T (Treg) CD4+CD25+FoxP3+subsets in patients with OSCC by multicoloured flow cytometry. Subsequently we investigated the effects their inhibition via TDG on growth of OSCC cell lines in vitro. An increased (p&lt;0.05) prevalence of Treg phenotypes (CD4+CD25+, CD4+FoxP3+, CD8+FoxP3+, CD4+CD25+FoxP3+) was observed in the peripheral circulation of OSCC patients that positively correlated with clinicopathological features. The increased frequency of CD4+CD8+CD25+FoxP3+, a unique T cell subset, CTLA4+, GITR+, NrP1+ and granzyme B+ (GzmB) Tregs also showed a significantly higher prevalence in OSCC patients. Functionally CD4+FoxP3+ Tregs showed skewed expression of IL2, IL10 and IL35 in patients as compared with the normal controls. Higher expression of TGFβ in tumor tissues suggests their dominant role in the up regulation of differentiation of Tregs from naive T cells in the tumor bearing host. Further, enhanced expression of CCR5 and CCR7 on Tregs with up regulation of their ligands (CCL5, CCL19 and CCL21) in tumor cells indicates efficient recruitment and trafficking of Tregs to the tumor site. Gal-1 expression was observed to be significantly higher in oral cancer patients. Treatment with βGBP showed growth promoting effects on Tregs and oral cancer cells. However, the treatment with its inhibitor TDG resulted in inhibition of Treg subsets and also decreased the frequency of IL10+ and IL35+ Tregs indicating its immunomodulatory effects. Hence, it seems reasonable to assume that modulation of functional dynamics of selective Treg subsets may be useful in enhancing anti tumor immunity and developing immunotherapeutic strategies for patients with oral squamous cell carcinoma.
Citation Format: Sadhna Aggarwal, Suresh C. Sharma, Satya N. Das. Significance of Treg cells in pathogenesis of oral squamous cell carcinoma [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO082.
Abstract PO084: Patterns of T cell clonal expansion in cancer patients associate with response to immunotherapy
Authors: Madireddi Shravan , Wu Thomas D. , de Almeida Patricia E. , Banchereau Romain , Chen Ying-Jiun J. , Chitre Avantika S. , Iftikhar Hina , O'Gorman William E. , Au-Yeung Amelia , Takahashi Chikara , Goldstein Leonard D. , Poon Chungkee , Keerthivasan Shilpa , Mariathasan Sanjeev , Das Thakur Meghna , Huseni Mahrukh A. , Ballinger Marcus , Estay Ivette , Caplazi Patrick , Modrusan Zora , Delamarre Lélia , Mellman Ira , Bourgon Richard , Grogan Jane L. 
Published: February 2021

Abstract
Upon encountering their cognate antigens, T cells can undergo clonal expansion to produce multiple copies of a cell with a shared T cell receptor (TCR). Despite the fundamental role of clonal expansion in cancer immunity, little is known about its relationship with T cell subpopulations or antitumor responses in cancer patients. Here we have performed single-cell RNA sequencing (scRNA-seq) and deep analysis of TCR clonotypes (scTCR-seq) in cancer patients across several indications, assessing the profiles of TCRs in the various populations of T cells in tumors, normal adjacent tissue (NAT), and peripheral blood. We found that, although most clonotypes were represented by a single cell, the remaining clonal lineages showed expansion in either NAT or tumor exclusively, or dual-residence with expansion in both compartments. In a subset of patients, we find clear evidence of clonotypic expansion of T effector- and effector memory-like cells not only within the tumor but also in NAT. Importantly, expanded clonotypes found in the tumor and NAT can also typically be detected in peripheral blood, suggesting a continuously replenishment from sites outside of the tumor with fresh, non-exhausted replacement cells. Our data further suggests a continued activity of the cancer immunity cycle in these patients, the acceleration of which may be associated with clinical response.
Citation Format: Shravan Madireddi, Thomas D. Wu, Patricia E. de Almeida, Romain Banchereau, Ying-Jiun J. Chen, Avantika S. Chitre, Hina Iftikhar, William E. O'Gorman, Amelia Au-Yeung, Chikara Takahashi, Leonard D. Goldstein, Chungkee Poon, Shilpa Keerthivasan, Sanjeev Mariathasan, Meghna Das Thakur, Mahrukh A. Huseni, Marcus Ballinger, Ivette Estay, Patrick Caplazi, Zora Modrusan, Lélia Delamarre, Ira Mellman, Richard Bourgon, Jane L. Grogan. Patterns of T cell clonal expansion in cancer patients associate with response to immunotherapy [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO084.
Abstract PO085: Cryogel-based cancer vaccine to treat acute myeloid leukemia
Authors: Najibi Alexander J. , Shah Nisarg J. , Shih Ting-Yu , Mao Angelo S , Sharda Azeem , Scadden David T. , Mooney David J. 
Published: February 2021

Abstract
Acute myeloid leukemia (AML) is a hematopoietic malignancy with limited therapeutic options. Standard-of-care chemotherapy depletes AML cells to induce remission, but often precedes disease relapse. To promote robust and durable immunity against AML, we developed a macroporous cryogel-based vaccine which provided a sustained release of GM-CSF to concentrate dendritic cells (DCs), TLR agonist CpG-ODN, and leukemia antigen. Prophylactic vaccination in mice against AML cell lysates or peptide antigen induced a potent anti-tumor adaptive immune response and prevented the engraftment of AML cells. This immunity was transferable, as bone marrow transplanted from vaccinated mice immunized recipients against AML. In models of established disease, only the combination of chemotherapy and biomaterial vaccination entirely eradicated AML in all mice and generated long-term T cell immunity preventing relapse. Notably, in combination with chemotherapy, a cryogel vaccine delivering no antigen (only GM-CSF and CpG-ODN) generated robust AML-specific T cell immunity, depleted leukemia, and enabled long-term survival. In this setting, tumor antigens were likely sourced from chemotherapy-induced AML cell death, as AML cells expressing high levels of apoptotic markers were found in the vaccine site and draining lymph node, co-localizing with DCs activated by the vaccine. These results demonstrate the capacity of a biomaterial-based vaccine to induce a potent immune response depleting AML and preventing relapse, even without defined antigen targets.
Citation Format: Alexander J. Najibi, Nisarg J. Shah, Ting-Yu Shih, Angelo S Mao, Azeem Sharda, David T. Scadden, David J. Mooney. Cryogel-based cancer vaccine to treat acute myeloid leukemia [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO085.