bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A87: Acetaminophen pretreatment stimulated interferon γ-induced PD-L1 protein expression in vitro and CD68 positive macrophage infiltration in tumor xenograft
Authors: Wu Jeffrey , Neuwelt Alexander J. , Muldoon Leslie L. , Neuwelt Edward A. 
Published: June 2021

Abstract
Immunotherapy targeting the programmed cell death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) pathway using antibodies is clinically effective in treating a spectrum of cancers. Acetaminophen (AAP) has shown antitumor and/or chemo-enhancing effects in human cancer cells in vitro and in vivo. We investigated the effects of AAP exposure on cancer cells’ immune checkpoint PD-L1 expression in vitro and their in vivo tumorigenic ability. Acetaminophen (10 mM) alone for 2 hr has no effect on cell viability and no effect on PD-L1 level of A2058 melanoma and H460 non-small cell lung carcinoma in vitro. However, AAP treatment for 2 hr followed by interferon-γ (20 ng/ml) stimulated PD-L1 protein expression. The stimulatory effect of AAP pretreatment was not replicated with other glutathione-depleting reagents, including hydrogen peroxide (100 μM; 2hr) or buthionine sulfoximine (50 μM; 24hr). For the in vivo tumorigenesis study, cancer cells (2.5x107) pretreated with AAP developed significantly (p=0.0028 in A2058 and p=0.002 in H460) smaller tumor size after being subcutaneously implanted into athymic rats. Compared to vehicle control, AAP also showed more tumor CD68+ macrophage infiltration by immunohistochemistry. Our results demonstrate for the first time the short-time exposure of AAP inhibited tumor growth by enhancing CD68+ macrophage infiltration. We conclude that high-dose AAP may be immune modulatory, a cell marker regulator and it could be potentially used as a single agent or in combination with other immunotherapy drugs to facilitate therapeutic efficacy.
Citation Format: Jeffrey Wu, Alexander J. Neuwelt, Leslie L. Muldoon, Edward A. Neuwelt. Acetaminophen pretreatment stimulated interferon γ-induced PD-L1 protein expression in vitro and CD68 positive macrophage infiltration in tumor xenograft [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 A87.
Abstract B02: Ephrin receptor A10 promotes PD-L1 expression for breast cancer immune evasion
Authors: Chan Li-Chuan , Cha Jong-Ho , Yang Wen-Hao , Xia Weiya , Lee Heng-Huan , Wang Ying-Nai , Hsu Jennifer L. , Ren Guoxin , Hung Mien-Chie 
Published: June 2021

Abstract
Programmed death-ligand 1(PD-L1) is an immune checkpoint protein and its engagement with programmed cell death protein-1 (PD-1) receptor on T cells activates co-inhibitory signaling to induce cancer immune evasion. PD-L1 or PD-1 blockade has demonstrated encouraging clinical outcomes in several advanced cancer treatment. Elucidating the regulatory mechanisms of PD-L1 is critical to improve the efficiency of PD-L1-targeting immunotherapy. Recent studies indicated that contact-dependent pathways downregulate anticancer immunity, highlighting the importance of cell contact-induced signaling for cancer immune escape. In this study, we show that tumor cell contact promotes PD-L1 expression and reduces immune surveillance via membrane receptor tyrosine kinase ephrin receptor A10 (EphA10), which is only expressed in normal testis tissue and mediates cell contact-dependent juxtacrine signaling. Abolishing the expression of EphA10 enhances T-cell-mediated antitumor immunity in 4T1 mouse model. A positive correlation between EphA10 and PD-L1 expression is observed in human breast cancer tissues. Overall, our findings indicate that cell contact-mediated juxtacrine signaling increases PD-L1 expression, suggesting that tumor cells avoid immune surveillance via this mechanism and blockade of EphA10 may be a new immunotherapy strategy for breast cancer patients.
Citation Format: Li-Chuan Chan, Jong-Ho Cha, Wen-Hao Yang, Weiya Xia, Heng-Huan Lee, Ying-Nai Wang, Jennifer L. Hsu, Guoxin Ren, Mien-Chie Hung. Ephrin receptor A10 promotes PD-L1 expression for breast cancer immune evasion [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 B02.
Abstract B07: Oncolytic adenovirus 3 coding for CD40L as an enhancer of dendritic cell therapy
Authors: Santos João Manuel , Hemminki Akseli , Siurala Mikko , Hemminki Otto , Havunen Riikka , Cervera-Carrascon Victor , Sorsa Suvi , Wang Hongjie , Lieber Andre , de Gruijl Tanja , Kanerva Anna , Zafar Sadia 
Published: June 2021

Abstract
Dendritic cell (DC) therapy is considered a promising immunotherapeutic approach for treatment of advanced cancer. However, the immunosuppressive tumor microenvironment leads to DC dysfunction. Therefore, in clinical trials DC therapy has generally failed to fulfill its expectations. Oncolytic adenoviruses are well tolerated and have shown to activate antitumor immune responses. Importantly, they can convert immunosuppression locally into a proinflammatory state. To improve the proper activation of transferred DCs, we armed oncolytic adenovirus with CD40 ligand (CD40L). CD40L is known to play an important role in the regulation of immune cells through its capacity to stimulate dendritic cells that leads to the activation of cytotoxic T cells. Therefore, we generated a novel virus Ad3-hTERT-CMV-hCD40L, which is fully serotype 3 adenovirus (Ad3) for intravenous delivery. It features a human telomerase reverse transcriptase (hTERT) promoter for tumor specific replication and expresses human CD40L (hCD40L) under a cytomegalovirus (CMV) promoter for induction of antitumor efficacy. Of note, human and animal data have shown the ability of Ad3 to successfully reach tumors through the intravenous route. In syngeneic studies in an immunocompetent model, DC therapy with our murine CD40L-armed adenovirus showed significant antitumor immune response. This enhanced therapeutic effect is associated with increased tumor specific T cells and induction of T-helper type 1 immune response. This synergistic effect was further evaluated in mice humanized with human peripheral blood mononuclear cells. Treatment with hCD40L-armed adenovirus and human DCs showed 100% survival in conjunction with tumor control. To conclude, CD40L armed oncolytic adenovirus 3 improves DC therapy by favorable alteration of tumor microenvironment. These findings support clinical trials where DC therapy is enhanced with oncolytic adenovirus.
Citation Format: João Manuel Santos, Akseli Hemminki, Mikko Siurala, Otto Hemminki, Riikka Havunen, Victor Cervera-Carrascon, Suvi Sorsa, Hongjie Wang, Andre Lieber, Tanja de Gruijl, Anna Kanerva, Sadia Zafar. Oncolytic adenovirus 3 coding for CD40L as an enhancer of dendritic cell therapy [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 B07.
Abstract B11: RAS orchestrates the increase of interstitial adenosine in lung adenocarcinoma to promote immune evasion
Authors: de Carné Sophie , East Philip , Moore Chris , Downward Julian 
Published: June 2021

Abstract
The RAS pathway is frequently activated in human cancers, including lung adenocarcinoma, leading to poor prognosis and resistance to therapy. Despite huge efforts, it is still not possible to target this pathway directly. In contrast, Immune checkpoint blockade has shown remarkable yet varied efficacy in lung cancer. With the aim of finding a vulnerable point in these aggressive tumors, we ask here whether oncogenic RAS shapes the immune landscape of lung adenocarcinoma. We classified human lung adenocarcinoma (LUAD) samples from the publicly available dataset from TCGA according to their RAS activity using a RAS transcriptional signature. We correlated the fraction of twenty-two types of leucocyte present in the samples with RAS activity using CIBERSORT. We also identified the expression of immune-related genes that were associated with RAS activity. We observed that RAS activity correlated with the recruitment of proinflammatory macrophages and neutrophils. RAS activity also correlated with the expression of several immune checkpoint genes (e.g., CD274 (PD-L1), HAVCR2 (TIM-3)) as well as genes related to adenosine metabolism or function (e.g., NT5E (CD73), SLC29A4 (ENT4)). Interstitial adenosine is known to dampen the antitumoral immune response. We validated that NT5E expression was dependent on the RAS-MAPK pathway in vitro in human lung cancer cell lines and in vivo in the KrasG12D-LSL/wt Trp53fl/fl mouse model of lung adenocarcinoma. RAS-active tumors could evade the immune system by increasing adenosine level in the tumor microenvironment, notably by increasing expression of CD73, the enzyme that converts extracellular AMP to adenosine. Patients with highly aggressive and resistant RAS-driven lung cancers could benefit from targeting adenosine metabolism (anti-CD73) or activity (A2AR inhibitors) in combination with other immunotherapies targeting PD-1/PD-L1 and TIM-3.
Citation Format: Sophie de Carné, Philip East, Chris Moore, Julian Downward. RAS orchestrates the increase of interstitial adenosine in lung adenocarcinoma to promote immune evasion [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 B11.
Abstract B12: Quantitative high-resolution tissue analysis defines intratumoral hot spots of PMN-MDSC activity in situ
Authors: Si Yu , Squire Anthony , Merz Simon , Bruderek Kirsten , Lang Stephan , Gunzer Matthias , Brandau Sven 
Published: June 2021

Abstract
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of myeloid cells with T-cell suppressive activity. While the identity and function of circulating MDSC is fairly well established in human cancer patients, the nature of potential MDSC in tissues remains largely enigmatic. However, understanding the biology of MDSC in human tissues is of pivotal importance, because MDSC are believed to regulate the activity of antitumor T cells and may serve as a major resistance mechanism in modern cancer immunotherapy. We developed a whole-mount tissue processing and staining procedure to mark PMN-MDSC subsets and T-cell effector function in situ in an intact 3-dimensional tissue architecture. We then used ultramicroscopy, digital image analysis and 3-D image reconstruction of original data to analyze and quantify the spatial distribution of MDSC and T cells. We identified intratumoral hot spots with high prevalence for both MDSC and T cells. T-cell effector function was reduced in these hot spots. Multicolor immunofluorescence and high-resolution image analysis also revealed the identity and frequency of cellular conjugates between MDSC and T cells. Quantitative spatial analyses indicated that immunosuppressive activity of MDSC requires close proximity of MDSC and T cells. Obtained data were applied to 2-D multicolor immunofluorescence analysis in a larger cohort of head and neck cancer patients with well-defined follow-up. Patients with evidence for strong downregulation of T-cell activity by PMN-MDSC presented with a significantly impaired survival, suggesting a clinical relevance of our findings. Our data suggest that co-targeting of PMN-MDSC and T cells could be beneficial in a subgroup of cancer patients. We also identified parameters useful to select those patients, who are likely to benefit from such immuno-combinations.
Citation Format: Yu Si, Anthony Squire, Simon Merz, Kirsten Bruderek, Stephan Lang, Matthias Gunzer, Sven Brandau. Quantitative high-resolution tissue analysis defines intratumoral hot spots of PMN-MDSC activity in situ [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 B12.
Abstract B17: Exosomal PD-L1 harbors active defense function to suppress T-cell activity and promote breast cancer tumor growth
Authors: Yang Yi , Li Chia-Wei , Chan Li-Chuan , Wei Yongkun , Hsu Jung-Mao , Xia Weiya , Cha Jong-Ho , Hou Junwei , Hsu Jennifer L. , Sun Linlin , Hung Mien-Chie 
Published: June 2021

Abstract
Tumor cell-derived exosomes play important roles in tumor-microenvironment regulations, and PD-L1 plays a passive protective role in the tumor microenvironment for tumor growth and progression. Our research revealed that PD-L1 exists in exosomes derived from human and mouse breast cancer cells and can be transferred to other cancer cells, rendering PD-L1-negative cancer cells PD-L1 positive and escape from T-cell killing. By binding to its receptor PD-1 to inhibit T-cell antitumor function, exosomal PD-L1 from cancer cells harbors active defense function to protect and promote tumor growth of breast cancer cells. Together with both genetic approach and pharmacologic inhibitor, the results suggested that blockage of exosome-PD-L1 secretion likely contribute significantly to antitumor immunity, and the combined inhibition of exosome secretion and anti-PD-L1 therapy has the potential to improve antitumor response in the clinic.
Citation Format: Yi Yang, Chia-Wei Li, Li-Chuan Chan, Yongkun Wei, Jung-Mao Hsu, Weiya Xia, Jong-Ho Cha, Junwei Hou, Jennifer L. Hsu, Linlin Sun, Mien-Chie Hung. Exosomal PD-L1 harbors active defense function to suppress T-cell activity and promote breast cancer tumor growth [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 B17.
Abstract B96: Pharmacodynamic studies of SB 11285, a systemically bioavailable STING agonist in orthotopic tumor models
Authors: Challa Sreerupa , Ramachandran Balaji , Vijayakrishnan Lalitha , Weitzel Douglas , Zhou Shenghua , Iyer Kris 
Published: June 2021

Abstract
Background: The activation of innate and adaptive immunity via Stimulator of Interferon Genes (STING) signaling is a potentially transformative immunotherapeutic strategy in cancer. We have previously reported that SB 11285 is a novel and highly potent STING agonist that can be delivered by intravenous, intraperitoneal and intratumoral routes. We report here the antitumor and pharmacodynamic studies of SB 11285 in multiple orthotopic and subcutaneous syngeneic mouse tumor models.
Methods: (1) Orthotopic NBT-II syngeneic rat bladder model: Rat bladder tumor cells were surgically implanted in the bladder wall of rats (n =10). After 6 days, SB 11285 was administered by i.v. @ 0.5, 1.5, and 3mg/kg on days 1, 5, 9,1 3, 17, 21, 25 and 31. Groups of rats treated with docetaxel at 7.5mg/kg i.v. and saline were used as positive and negative controls, respectively. At the end of dosing period, the bladders were harvested and evaluated by measurement of bladder weight and gross pathology. (2) Pharmacodynamic (PD) studies: Syngeneic mouse subcutaneous CT26 colon carcinoma and orthotopic 4T1 breast cancer models were used. In the CT26 model, when mean tumor volume (MTV) reached 125mm3, SB 11285 was administered at 3mg/kg i.v on days 1 and 5. In the orthotopic 4T1 model, SB 11285 was administered i.p. @ 10mg/kg on days 5, 7, 9, 11, 13, 17 and 19. Blood, lymph nodes, spleen and tumor were harvested and evaluated for (i) cytokine analysis by multiplexing assays and (ii) enumeration of CD4+, CD8+, Tregs, macrophages and MDSCs in blood, lymph nodes, spleen and tumor.
Results: (1) In the orthotopic NBT-II rat bladder study, animals that received SB 11285 in all doses remained tumor-free based upon gross pathology and bladder weight measurements. SB 11285 was shown to be well tolerated and safe. (2) In both the 4T1 and CT26 PD studies, cytokine analysis of blood and tissues showed strong induction of type I interferon signature without significant systemic inflammatory response. Flow cytometric analysis of blood, lymph nodes, spleen and tumor revealed significant increase in macrophage & CD8+ T-cell infiltration and decrease in Tregs & CD4+ T-cell infiltration.
Conclusion: SB 11285 showed potent antitumoral activity in multiple orthotopic and subcutaneous models that correlated with antitumoral immune response mediated by the induction of IFNs, and ISGs and other cytokines along with reduction of Tregs. SB 11285 is being advanced to human clinical trials.
Citation Format: Sreerupa Challa, Balaji Ramachandran, Lalitha Vijayakrishnan, Douglas Weitzel, Shenghua Zhou, Kris Iyer. Pharmacodynamic studies of SB 11285, a systemically bioavailable STING agonist in orthotopic 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 B96.
Abstract IA06: Tumor and host factors regulating antitumor immunity and immunotherapy efficacy
Authors: Gajewski Thomas F. 
Published: June 2021

Abstract
Two major phenotypes of human melanoma metastases have been observed based on gene expression profiling and confirmatory assays. One subgroup of patients has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and appears to display immune “exclusion.” The mechanisms of immune escape are likely distinct in these two subsets, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3+ Tregs. Deep analysis of tumor antigen-specific T cells in the tumor microenvironment has identified additional mechanisms of immune dysfunction and new potential therapeutic targets. Treatment strategies targeting several pathways have been translated back into the clinic, with anti-PD-1/PD-L1 agents being FDA approved for 11 different cancer entities. Combinations with new agents based on the biology of T-cell dysfunction are ongoing. In contrast to the T cell-inflamed melanomas, non-T cell-inflamed tumors are largely immunotherapy resistant with current approaches. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via CD8+ DCs, and these factors are absent in non-T cell-inflamed tumors. New strategies are being developed to engage or mimic this pathway as a therapeutic endeavor, including STING agonists. The molecular mechanisms that mediate the absence of the T cell-inflamed tumor microenvironment in patients are being elucidated using parallel genomics platforms. The first oncogene pathway identified that mediates immune exclusion is the Wnt/β-catenin pathway, which argues that new pharmacologic strategies to target this pathway should be developed to restore immune access to the tumor microenvironment. Recent evidence has indicated that host factors, including the intestinal microbiota, are also critical. We recently have identified commensal bacteria in mouse models that augment spontaneous antitumor immunity and increase efficacy of anti-PD-L1 therapy. Similar analyses in human melanoma patients revealed commensal bacteria associated with anti-PD-1 efficacy. These results have prompted the pursuit of new probiotics that may improve spontaneous immune infiltration and expand immunotherapy efficacy in the clinic.
Citation Format: Thomas F. Gajewski. Tumor and host factors regulating antitumor immunity and immunotherapy efficacy [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 IA06.
Abstract IA20: Immune checkpoint blockade in cancer therapy: New insights and opportunities, and prospects for cures
Authors: Allison James P. 
Published: June 2021

Abstract
The existence of multiple nonredundant inhibitory pathways that limit T-cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits T-cell proliferation by interfering with the interaction of the costimulatory molecule CD28 with its ligands B7-1 and B7-2 on the surface of antigen-presenting cells. Antibodies to CTLA-4 have proved effective against multiple tumor types in both preclinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long-term (&gt;4 years) survival benefit in about 20% of patients in a randomized, placebo-controlled trial in late-stage melanoma. In 2011 it was approved by the FDA for treatment of late-stage melanoma, and it remains part of the standard of care for that disease. PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T-cell antigen receptor-mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25%. Combination of anti-PD-1 and anti-CTLA-4 in melanoma provides objective responses in about 50% of late-stage melanoma patients. The FDA has now approved 6 different checkpoint antibodies for a variety of cancers including urothelial, renal, and lung cancers. A major focus of current efforts is the rational identification of combinatorial treatments that improve the response rate and expand the range of immune checkpoint inhibitors. We used high-parameter flow cytometry to identify the mostly nonoverlapping cellular mechanisms of CTLA-4 and PD-1 blockade, which may partially explain the enhanced effect of their combination. Further work has shown that combined CTLA-4 and PD-1 blockade, which provides higher response rates against a wider range of cancers than either monotherapy, acts through a population of T cells not enriched in either single treatment. T-cell responses are largely directed toward neoantigens arising as a result of mutational events associated with the carcinogenesis. While all tumors with antigens recognizable by the immune system should be targets for checkpoint blockade, tumors with lower burdens of mutations (e.g., prostate, breast, and kidney cancer) present special challenges for immune therapy. Recent evidence suggests that even the few neoantigens carried by these can provide targets for immune attack. Strategies for effective treatment of such tumors will be discussed.
Citation Format: James P. Allison. Immune checkpoint blockade in cancer therapy: New insights and opportunities, and prospects for cures [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 IA20.