bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract TMIM-068: TARGETING ER STRESS RESPONSES TO UNLEASH THERAPEUTIC IMMUNITY AGAINST OVARIAN CANCER
Authors: Cubillos-Ruiz Juan R 
Published: June 2021

Abstract
Harnessing the intrinsic ability of our immune system to eliminate malignant cells represents the most promising new anti-cancer strategy since the development of chemotherapy. While cancer immunotherapy has been designated a scientific breakthrough, tumor-induced immunosuppression still represents a major impediment to the success of this new approach in the vast majority of cancer patients. We found that ovarian cancer inhibits the development of protective anti-tumor immunity by inducing a state of continued “Endoplasmic Reticulum (ER) Stress” in tumor-associated dendritic cells (tDCs). Sustained activation of the IRE1-XBP1 arm of the ER stress response in DCs was necessary for the aggressive and accelerated progression of primary and metastatic ovarian cancers in various preclinical models of disease. Mechanistically, hyperactive XBP1 disrupted crucial metabolic pathways in tDCs and caused severe immune cell dysfunction at tumor sites. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective T cell-mediated anti-tumor immunity. Our findings uncover a new regulatory role for XBP1-driven signaling in DCs of the tumor microenvironment and suggest that targeting aberrant ER stress responses may represent a new strategy to unleash protective immune responses against ovarian cancer.
Citation Format: Juan R, Cubillos-Ruiz. TARGETING ER STRESS RESPONSES TO UNLEASH THERAPEUTIC IMMUNITY AGAINST OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-068.
Abstract TMIM-070: APELIN PROMOTES OMENTAL METASTASIS OF OVARIAN CANCER CELLS
Authors: Dogra Samrita , Neelakantan Deepika , Patel Maulin Mukeshchandra , Griesel Beth , Olson Ann , Lupu Florea , Wool Sukyung 
Published: June 2021

Abstract
PURPOSE: Ovarian cancer (OvCa) is mainly metastasized to the peritoneal cavity and omentum, an organ primarily composed of adipocytes. Adipocytes produce adipokines including apelin involved in initiating angiogenesis and promote the initial homing of tumor cells to omentum through adipokine secretion. Apelin and its receptor APJ mediates glucose/energy metabolism and angiogenesis. The study objective is to assess the functional role of apelin/APJ pathway in omental metastasis of OvCa and associated benefits from antagonizing this pathway as a novel treatment strategy against OvCa metastasis.
METHODS: Mouse adipocyte cell line 3T3-L1 were used to obtain adipocyte-derived conditioned media (adipo-CM). Apelin concentrations in adipo-CM were quantified using Western blot and ELISA. Migration and invasion of human OvCa cell lines (OVCAR-5APJ and OVCAR-8) were determined in vitro in the presence of adipo-CM. In vivo homing and ex vivo adhesion assays were performed to study the role of apelin/APJ pathway in attracting and attaching APJ-overexpressing OvCa cells to the omentum.
RESULTS: Apelin expression was 2.5 fold higher in mature adipocytes compared to that in pre-adipocytes. Mature adipocytes secreted 0.8-1 ng/mL of apelin in the CM. In vivo, high APJ expression increased 'homing-in' of OvCa cells by 2.75-fold to the omentum. Adipo-CM increased transwell migration (3-3.5 fold) and invasion (3.5-4 fold) of OvCa cells in vitro. Adhesion of APJ high expression OvCa cells to mice omentum ex vivo increased by 1.5 fold. These apelin-induced pro-metastatic effects were reversed by apelin-specific antagonist (F13A) in a dose-dependent manner.
CONCLUSION: We found that apelin/ APJ pathway potentially promotes OvCa metastasis to omentum and F13A effectively inhibited apelin-induced effects.
Citation Format: Samrita Dogra, Deepika Neelakantan, Maulin Mukeshchandra Patel, Beth Griesel, Ann Olson, Florea Lupu, and Sukyung Woo1. APELIN PROMOTES OMENTAL METASTASIS OF OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-070.
Abstract TMIM-076: OMENTAL MACROPHAGES REGULATE OVARIAN CANCER METASTATIC COLONIZATION THROUGH THE CCL6-CCR1 SIGNALING AXIS
Authors: Krishnan Venkatesh , Tallapragada Supreeti , Schaar Bruce , Chanana Anita , Rinker-Schaeffer Carrie , Dorigo Oliver 
Published: June 2021

Abstract
BACKGROUND: Metastatic ovarian cancer remains an urgent clinical problem. The homing and invasion of cancer cells into the omental adipose tissue, which is the preferred site of ovarian cancer metastasis, is a critical step in disease progression. Omental adipose tissue contains adipocytes, blood vessels, and clusters of leukocytes known as milky spots. We have previously demonstrated in several mouse models that intraperitoneally injected ovarian cancer cells localize to the omentum and specifically to the milky spots. However, we found that B, T, or NK cells were not required for omental colonization. We hypothesize that macrophages within the milky spots play a crucial role in promoting ovarian cancer progression.
METHODS AND RESULTS: Depleting macrophages disrupts cancer cells' localization to the omentum. This result supports our hypothesis that macrophages play an essential role in attracting ovarian cancer cells to the omental milky spots. Correspondingly, factors secreted by omental macrophages promote ovarian cancer migration in vitro, in contrast to factors secreted by macrophages isolated from other peritoneal adipose tissues. In order to understand the specific mechanism(s) that regulate metastatic colonization of the omentum, we performed RNA-Seq of CD45+CD11b+F4/80+ flow-sorted macrophages from the omentum and the mesenteric fat of naïve and cancer-bearing mice. We found that omental macrophages have a distinct and dynamic gene expression pattern even when compared to a very similar cell type. The chemokine CCL6 is one of the most highly upregulated genes during metastatic colonization. The human homolog of CCL6 is CCL23 and is also expressed by human omental macrophages. Genomic inactivation of CCR1, the gene encoding receptor for CCL6 in mice and CCL23 in humans, in mouse ovarian cancer cells abolishes their ability to home to omental milky spots. Our findings establish a role for chemokine signaling in the early colonization of the omentum by ovarian cancer.
CONCLUSION: We demonstrate that omental milky spots are the preferential sites for cancer colonization of peritoneal adipose. Further, we have identified omental macrophages as the critical mediators of colonization via the CCL6/CCR1 chemokine axis. Future studies are focused on understanding the cancer cell-macrophage interactions that can be targeted therapeutically to disrupt metastatic growth and extend disease-free survival.
Citation Format: Venkatesh Krishnan, Supreeti Tallapragada, Bruce Schaar, Anita Chanana, Carrie Rinker-Schaeffer, Oliver Dorigo. OMENTAL MACROPHAGES REGULATE OVARIAN CANCER METASTATIC COLONIZATION THROUGH THE CCL6-CCR1 SIGNALING AXIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-076.
Abstract A06: Direct and indirect effects of low-dose radiation on Tregs and antitumor efficacy among diverse tumor models
Authors: Simon Samantha , Garnett-Benson Charlie 
Published: June 2021

Abstract
The impact of radiation on TREG cells remains controversial. Radiation has been shown by our lab, and others, to alter the phenotype of human tumor cell by enhancing their expression of the co-stimulatory molecules OX-40L and 4-1BBL. Both OX-40 and 4-1BB signaling have been reported to influence TREG frequency and function, and we hypothesized that radiation-induced changes in expression of these molecules could influence the frequency of TREG cells within tumors. We evaluated three widely used murine tumor models for these experiments. 4T1 (mammary), MC38 (colon), or CT26 (colon) cells were implanted s.c. into mice and treated locally with 8-10Gy of radiation. Several days after treatment the frequency of tumoral T cells, including CD4+Foxp3+ TREG cells, was evaluated by fluorescent IHC and flow cytometry. We found that radiation differentially impacted the frequency of TREGS among the three tumor models evaluated and appeared to correlate with expression levels of 4-1BBL and OX-40L on the tumor cells post-IR. The level of tumor control post-RT also mirrored expression levels of 4-1BBL and OX-40L on tumor cells. Interestingly, 4T1 tumors contained more total CD4+ cells within tumors, but contained less TREG cells within the CD4 population, after radiation as compared to MC38 tumors. 4T1 tumor-bearing mice also contained more CD4+41BB+ cells as compared to MC38 tumor-bearing mice. These differences may contribute to differences in the therapy responses of various murine models utilizing radiation and may serve as useful biomarker to predict antitumor responses post-IR.
Citation Format: Samantha Simon, Charlie Garnett-Benson. Direct and indirect effects of low-dose radiation on Tregs and antitumor efficacy among diverse tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A06.
Abstract A07: Assessment of concordance among 22C3, SP263, and SP142 immunohistochemistry assay for PD-L1 expression in non-small cell lung cancer
Authors: Jung Chi Young , Kim Eun Jin , Sung Woo Jung 
Published: June 2021

Abstract
Background: PD-L1 expression, as determined by immunohistochemistry (IHC), is the most commonly use predictive biomarker for anti-PD-1 and anti-PD-L1 agents in currently available in clinical practice. However, multiple antibodies have been utilized in IHC assays and interpretation of their results has not been standardized. Recently, several studies have compared different antibodies and IHC systems for PD-L1 tests. We aimed to evaluate the similarity and concordance between three validated, commercially available PD-L1 IHC assays for non-small cell lung cancer (Dako 22C3, Ventana SP263, and Ventana SP142).
Methods: We evaluated 219 samples from patients with non-small cell lung cancer at the Daegu Catholic University Medical Center between June 2017 and July 2018. Each tumor sample was stained with PD-L1 IHC 22C3, SP263, and SP142. PD-L1 expression was scored at different cut-off levels for each IHC antibodies (22C3 assay: &lt;1%, 1-49%, and ≥50%, SP263: &lt;10%, ≥10 and &lt;25%, and ≥25%, SP142: &lt;1%, 1-4%, 5-49%, and ≥50%).
Results: Among the 219 samples, three different antibodies showed well correlation for PD-L1 expression (22C3 vs. SP263; r=0.896, p&lt;0.001, 22C3 vs. SP142; r=0.750, p&lt;0.001, SP263 vs. SP142; r=0.728, p&lt;0.001). 22C3 IHC assay produced the similar results with SP263 IHC assay (Kappa value=0.510, p&lt;0.001). However, 22C3 vs. SP263 and SP263 vs. SP142 showed poor concordance (Kappa value=0.171, p=0.004, and Kappa value=0.240, p&lt;0.001, respectively).
Conclusions: 22C3, SP263, and SP142 IHC assays showed good correlation for PD-L1 expression. 22C3 IHC assay showed good concordance with SP263, but SP142.
Citation Format: Chi Young Jung, Eun Jin Kim, Woo Jung Sung. Assessment of concordance among 22C3, SP263, and SP142 immunohistochemistry assay for PD-L1 expression in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A07.
Abstract A08: Adenovirus coding for TNF-α and IL-2 proteins mediates abscopal effect in mice receiving anti-PD1 immunotherapy
Authors: Quixabeira Dafne C.A. , Cervera-Carrascón Víctor , Havunen Riikka , Siurala Mikko , Hemminki Akseli 
Published: June 2021

Abstract
Background: Treatment of multiple tumors and metastasis remains a challenge for current therapeutic approaches in cancer treatment. Some responses in noninjected metastases were described in the middle of the last century after using local radiotherapy in breast cancer patients. This phenomenon was named abscopal effect. Nowadays, this effect is well known to be elicited by systemic adaptive immune responses against tumor cells. Of note, it has not been fully reproducible in the clinic mainly due to the suppressive microenvironment surrounding cancer cells. The systemic use of immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1, has shown promise in the treatment of many tumors, but a minority of patients respond. Oncolytic virotherapy is a promising strategy that has emerged in the last few decades. It is able to prime the host immune system against tumor epitopes, thus theoretically complementing aPD1 therapy in an appealing manner. The challenge with oncolytic immunotherapy is that not all metastases can usually be injected. Therefore, it is of importance to study if local treatment can induce distant responses. While our previous work has shown synergy between oncolytic adenovirus and aPD1, here we sought to establish if the synergy extends to noninjected tumors.
Aim: In the present study we aimed to assess if local adenovirus injection can impact also noninjected tumors in animals receiving aPD1 therapy.
Methods: We utilized a murine melanoma model (B16.OVA) in which each mouse has two tumors, where only one tumor receives local virotherapy and the secondary tumor is studied for possible systemic effects following local injection.
Results: Improvement in the overall survival was seen in the group using both therapies (aPD-1 plus virus) compared to the single therapies alone. As well, secondary tumor growth was better controlled in that group. Further information, including the final survival curve, tumor growth and immunologic mechanism-of-action data, will be presented.
Conclusion: These two cancer immunotherapeutics seem to be a promising dynamic approach that may increase the life expectancy and cure the patients suffering from metastatic cancer when translated to the clinic, besides minimizing considerably the toxicity due to the specificity of such approach, and finally improving patients’ quality of life during the treatment.
Citation Format: Dafne C.A. Quixabeira, Víctor Cervera-Carrascón, Riikka Havunen, Mikko Siurala, Akseli Hemminki. Adenovirus coding for TNF-α and IL-2 proteins mediates abscopal effect in mice receiving anti-PD1 immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A08.
Abstract A32: The SUV39H1-H3K9me3 pathway represses cytotoxic T lymphocyte effector expression to confer colon carcinoma immune escape
Authors: Lu Chunwan , Yang Dafeng , Klement John D. , Oh Kyu , Savage Natasha M. , Waller Jennifer L. , Colby Aaron H. , Grinstaff Mark W. , Oberlies Nicholas H. , Pearce Cedric , Xie Zhiliang , Kulp Samuel , Coss Christopher , Phelps Mitch A. , Albers Thomas , Lebedyeva Iryna O. , Liu Kebin 
Published: June 2021

Abstract
Despite the presence of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment, the majority of immunogenic human colon cancers do not respond to immune checkpoint inhibitor immunotherapy and microsatellite instable (MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unknown. We report here that CTLs are present in both MSI and microsatellite stable (MSS) colon tumors. The expression of the H3K9me3-specific histone methyltransferase SUV39H1 is significantly elevated in human colon carcinoma as compared to normal colon tissues. Using a mouse colon carcinoma model, we further determined that tumor-infiltrating CTLs in the colon tumor microenvironment express high levels of SUV39H1. To target SUV39H1 in the tumor microenvironment, a virtual chemical library was screened based on the SET domain structure of human SUV39H1 protein. Functional enzymatic activity assays identified a small molecule that inhibits SUV39H1 enzymatic activity. Based on the structure of this small molecule, we modified it and chemically synthesized a novel small molecule, termed F5446, which has an EC50 of 0.496 μM for SUV39H1 enzymatic activity. H3K9me3 is enriched in the promoters of GZMB, PRF1, FASLG and IFNG in quiescent T cells. F5446 inhibits H3K9me3, thereby upregulating expression of these effectors in tumor-infiltrating CTLs and suppressing colon carcinoma growth in a CD8+ CTL-dependent manner in vivo. Our data indicate that SUV39H1 represses CTL effector expression and, in doing so, confers colon cancer immune escape.
Citation Format: Chunwan Lu, Dafeng Yang, John D. Klement, II Kyu Oh, Natasha M. Savage, Jennifer L. Waller, Aaron H. Colby, Mark W. Grinstaff, Nicholas H. Oberlies, Cedric Pearce, Zhiliang Xie, Samuel Kulp, Christopher Coss, Mitch A. Phelps, Thomas Albers, Iryna O. Lebedyeva, Kebin Liu. The SUV39H1-H3K9me3 pathway represses cytotoxic T lymphocyte effector expression to confer colon carcinoma immune escape [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A32.
Abstract A33: The next-generation BET inhibitor, PLX51107, delays melanoma growth, altering the tumor immune microenvironment via Cox2 inhibition
Authors: Erkes Dan A. , Field Conroy O. , Capparelli Claudia , Tiago Manoela , Purwin Timothy J. , Heilman Shea A. , Chervoneva Inna , Berger Adam C. , Rosenbaum Sheera R. , Hartsough Edward J. , Villanueva Jessie , Aplin Andrew E. 
Published: June 2021

Abstract
Epigenetic agents such as bromodomain and extra terminal domain inhibitors (BETi) slow tumor growth via tumor intrinsic alterations; however, their effects on antitumor immunity remain unclear. A recent advance is the development of next-generation BETi that are potent and display a favorable half-life. Here, we tested the next-generation BETi, PLX51107, for immune-based effects on tumor growth in BRAF V600E melanoma syngeneic models. PLX51107 delayed melanoma tumor growth to differing degrees and altered the immunogenicity by lowering PD-L1 and FasL and increasing MHC-I in highly responsive melanomas. Moreover, PLX51107 treatment increased activated, proliferating and functional CD8+ T cells in tumors, leading to CD8+ T-mediated tumor growth delay. PLX51107 led to increased CD8-promoting, antitumor dendritic cells by acting as a Cox2 inhibitor. The accumulation of CSF-1R+ tumor-associated macrophages in poorly responsive melanoma limited PLX51107 efficacy. Importantly, PLX51107 delayed the growth of tumors that progressed on anti-PD-1 therapy, a response associated with decreased Cox2 levels, decreased PD-L1 expression and increased MHC-I expression on nonhematopoietic cells and increased intratumoral CD8+ T cells. Thus, next-generation BETi represent a potential first-line and secondary treatment strategy for metastatic melanoma by eliciting effects, at least in part, on antitumor immunity.
Citation Format: Dan A. Erkes, Conroy O. Field, Claudia Capparelli, Manoela Tiago, Timothy J. Purwin, Shea A. Heilman, Inna Chervoneva, Adam C. Berger, Sheera R. Rosenbaum, Edward J. Hartsough, Jessie Villanueva, Andrew E. Aplin. The next-generation BET inhibitor, PLX51107, delays melanoma growth, altering the tumor immune microenvironment via Cox2 inhibition [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A33.
Abstract A36: CXCL14-mediated antigen-specific CD8+ T-cell responses suppress HPV-positive head and neck cancer
Authors: Westrich Joseph A. , Vermeer Daniel W. , Bonney Stephanie , Silva Alexa , Berger Jennifer N. , Madeo Marianna , Cicchini Louis , Lee John H. , Spanos William C. , Pyeon Dohun 
Published: June 2021

Abstract
Human papillomaviruses (HPVs) cause over 5% of all human cancer incidences, including a subset of head and neck squamous cell carcinoma (HNSCC), resulting in about half a million deaths every year. Persistent infection with high-risk HPV is necessary for development of HPV-associated malignancies. To establish persistence in the host, HPV must evade host antiviral defenses, including the innate and adaptive immune responses. As antiviral and antitumor immune responses share similar mechanisms, it is likely that HPV-induced immune suppression leads to immune evasion and survival of HPV-infected cancer cells. We have previously shown that expression of the chemokine CXCL14 is significantly downregulated by promoter methylation mediated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive HNSCC cells dramatically suppresses tumor growth through an immune-dependent mechanism in mice. While CXCL14 recruits NK and CD8+ T cells to the tumor microenvironment, the roles of NK and T cells to enact the CXCL14-mediated tumor suppression remained undefined. To determine the roles of NK and CD8+ T cells, tumor growth was assessed in wild-type C57BL/6 mice depleted of NK or CD8+ T cells and CD8-knockout mice injected with the HPV-positive HNSCC cells re-expressing CXCL14. The results show that that CD8+ T cells are required for CXCL14-mediated tumor suppression. The antitumor CD8+ T-cell responses require antigen specificity as a transgenic model of mice with a restricted CD8+ T-cell receptor failed to control tumor growth. Counteracting the HPV-mediated downregulation of major histocompatibility complex class I (MHC-I), CXCL14 expression restores MHC-I expression on HPV-positive HNSCC cells. Furthermore, knockdown of MHC-I expression in CXCL14 expressing HNSCC cells results in loss of tumor suppression, defining a critical role for antigen presentation. These results suggest that CXCL14 expression drives antigen-specific CD8+ T-cell responses and suppresses tumor growth through the restoration of MHC-I expression in HPV-positive HNSCC. Our findings provide useful insight into the CXCL14-mediated antitumor mechanism that increases CD8+ T-cell recognition of tumor cells and could boost the efficacy of current immunotherapies.
Citation Format: Joseph A. Westrich, Daniel W. Vermeer, Stephanie Bonney, Alexa Silva, Jennifer N. Berger, Marianna Madeo, Louis Cicchini, John H. Lee, William C. Spanos, Dohun Pyeon. CXCL14-mediated antigen-specific CD8+ T-cell responses suppress HPV-positive head and neck cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A36.