bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA05: Innate immune defenses against cancer: Potential for mobilizing NK cells for cancer immunotherapy
Authors: Raulet David H. 
Published: February 2021

Abstract
Immunotherapies that mobilize CD8 T cells have revolutionized cancer therapy in recent years. A likely limitation of CD8 T cells in immunotherapy is that many tumors display few neoantigens and/or lack MHC I expression. Natural killer cells have emerged as exciting targets for new generations of immunotherapeutics. We investigated innate cues necessary for mobilizing spontaneous anti-tumor responses against tumors in mice and identified the cGAS-STING pathway as a critical pathway that is activated by cancer cells and mobilizes both NK cell and T cell mediated tumor rejection. Cyclic dinucleotides (CDNs) are STING agonists that, when injected into tumors, superactivate cellular immunity. We investigated the efficacy of CDNs in mobilizing anti-tumor activity in 6 independent gene edited models of MHC I-deficient tumors. Due to the absence of MHC I, CD8 T cells played no role in these responses. When transplanted syngeneic tumors of all 6 models were established and then treated intratumorally with CDNs (a single treatment, or in some cases 3 early treatments), tumor rejection rapidly ensued, which was NK-dependent and independent of CD8 T cells. In 5 of 6 MHC I-deficient tumor models tested, CDN therapy resulted in the indefinite survival of between 30% and 100% of the animals, with no evidence of residual tumors, suggesting the animals were cured. In one model (MHC I-deficient B16 melanoma cells) early rejection of the tumors was followed by relapse in all of the animals. Tumor rejection induced by CDNs was IFN-I-dependent, and conditional knockout experiments indicated that IFN-I acted directly on NK cells but also indirectly on DCs. After CDN therapy, DCs in the draining lymph nodes upregulated IL-15/IL-15R complexes on the membrane, and tumor rejection was blocked by neutralizing IL-15/IL15R. These data suggested that CDNs induce trans-presentation of IL15 by DCs to NK cells to support the tumor rejection response. CDN-induced tumor rejection was markedly enhanced by combining CDNs with IL-2 superkine (“super2”, in collaboration with C. Garcia), resulting in long-term tumor free survival in nearly all of the mice in the MHC I-deficient B16 and MC-38 models, indicating striking synergy between CDNs and super2. Our results suggest great potential for combining agonists of innate immune responses with superkines for treating cancers that are invisible to CD8 T cells, including MHC I-deficient cancers and potentially cancers with low neoantigen expression.
Citation Format: David H. Raulet. Innate immune defenses against cancer: Potential for mobilizing NK cells for cancer 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 IA05.
Abstract IA07: The QuEST for an effective immunotherapy for prostate cancer
Authors: Gulley James L. 
Published: February 2021

Abstract
Background: Immune checkpoint inhibitors have minimal activity in unselected CRPC patients (pts). Combination regimens that generate a tumor-directed immune response (vaccine) and facilitate the resulting anti-tumor immune activity (checkpoint blockade, cytokines) have shown synergy in preclinical models. BNVax is a therapeutic poxviral vaccine targeting brachyury, a transcription factor involved in invasion and metastasis. BA is a bifunctional fusion protein: anti-PD-L1 monoclonal antibody fused to the TGFb-β-RII receptor extracellular domain (a TGF-β trap). N-803 is an IL-15 superagonist complex. Here we report an interim efficacy analysis of the QuEST1 study, aimed to rapidly interrogate safety and efficacy of immunotherapy combinations in CRPC. Methods: Asymptomatic/minimally symptomatic CRPC pts received BNVax + BA (Arm 2.1) or BNVax + BA + N-803 (Arm 2.2). BNVax is given as 2 prime doses followed by boosts. BA 1,200 mg intravenously and N-803 15 µg/kg subcutaneously are given every 2 weeks. Efficacy is defined as objective response by RECIST v1.1 or PSA decrease ≥ 30% sustained for ≥ 21 days. Safety was a secondary endpoint. Results: As of 10/11/20, 26 CRPC pts enrolled and had 1 to 23 months follow up. 1/13 pts (Arm 2.1) had a PSA response sustained for 13 months. 5/12 (41.6%) pts on treatment for at least 12 weeks (Arm 2.2) had sustained PSA responses, including 2 pts who progressed on enzalutamide. Of 3 patients with measurable disease, 2 had confirmed PR by RECIST. Grade 3 TRAEs: 1 pancreatitis (Arm 2.1), 1 secondary adrenal insufficiency (Arm 2.1), 1 tumor hemorrhage (Arm 2.1), 1 hyperglycemia due to new onset diabetes mellitus (Arm 2.2), 1 cystitis (Arm 2.2), 1 Rash with eosinophilia (Arm 2.2). One patient had grade 4 neutropenia that resolved with growth factor support and oral corticosteroids. Conclusions: BVax + BA + N-803 demonstrated a manageable safety profile and preliminary evidence of efficacy in CRPC. Addition of N-803 in Arm 2.2 was associated with more activity in this small sample. Arm 2.2 met the predetermined threshold for efficacy and will expand (n=25).
Citation Format: James L. Gulley. The QuEST for an effective immunotherapy for prostate cancer [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 IA07.
Abstract IA11: Viral vectored vaccines for prostate cancer
Authors: Hill Adrian V. S. , Tuthill M. , Cappuccini F. , Carter L. , Pollock E. , Poulton I. , Verrill C. , Evans T. , Marshall M. , Gillessen S. , Attard G. , Protheroe A. , Hamdy F. , Redchenko I. 
Published: February 2021

Abstract
New therapeutic antigen-specific approaches are required to generate and sustain therapeutic immune responses against tumour specific antigens in cancer. Based on twenty years of experience with attempt to maximise the induction of potent T cell responses against infectious pathogens in humans we have begun to assess the utility of non-replicating viral vectors in cancer. Two trials in prostate cancer patients have completed enrolment and another in lung cancer is planned. We have reported efficacy data for a novel vaccine based on two replication-deficient viruses, chimpanzee adenovirus (ChAdOx1) and MVA, targeting an oncofetal self-antigen 5T4, administered as a single agent and in combination with anti-PD-1 in mouse tumour models. Based on recently reported encouraging safety and exceptional T cell immunogenicity in a phase I “VANCE” study (NCT02390063) of me with localised prostate cancer, the phase I/II trial, ADVANCE (NCT03815942) was undertaken to test vaccine safety and efficacy in combination with PD-1 blockade in metastatic prostate castrate-resistant cancer (mCPRC). We find a satisfactory safety profile for the use of these viral vectored vaccines with anti-PD1 in mCRPC patients but with lower immunogenicity than in localised prostate cancer patients. However, an encouraging response rate, as measured the reduction in PSA levels by 50%, was observed in this trial and options for enhancing immunogenicity and efficacy further will be discussed.
Citation Format: Adrian V. S. Hill, M. Tuthill, F. Cappuccini, L. Carter, E. Pollock, I. Poulton, C. Verrill, T. Evans, M. Marshall, S. Gillessen, G. Attard, A. Protheroe, F. Hamdy, I. Redchenko. Viral vectored vaccines for prostate cancer [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 IA11.
Abstract IA16: Discovery of new immunotherapy targets and mechanisms leveraging CRISPR
Authors: Sharpe Arlene H. 
Published: February 2021

Abstract
This talk discusses a CRISPR-Cas9 based platform for in vivo screening of immune genes. This platform facilitates discovery of regulators of tumor immunity and targets for combination therapy. We will discuss the use of this platform to perform in vivo CRISPR-based screens to enable rapid discovery of therapeutic targets in immune cells, and our identification of Ptpn2 as a negative regulator of exhausted CD8+ T cell responses using this CRISPR platform.
Citation Format: Arlene H. Sharpe. Discovery of new immunotherapy targets and mechanisms leveraging CRISPR [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 IA16.
Abstract PO010: The inhibition of IWS1 phosphorylation promotes genomic instability, the cGAS/STING pathway activation and PD-L1 levels, through the U2AF2 alternative RNA splicing and Sororin expression
Authors: Laliotis Georgios I. , Chavdoula Evangelia , Kaba Abdul , La Ferlita Alessandro , Anastas Vollter , Orlacchio Arturo , Sehgal Lalit , Carbone David P. , Coppola Vincenzo , Tsichlis Philip N. 
Published: February 2021

Abstract
We have previously shown that the loss of IWS1 phosphorylation promotes the alternative RNA splicing of U2 Associated-Factor 2 (U2AF2), resulting in transcripts lacking exon 2 in lung adenocarcinoma cells. This exon encodes part of the U2AF65 Serine-Rich (SR) Domain, which is required for its binding with pre-mRNA Processing factor 19 (Prp19). We have also shown that inhibition of the pathway results in the downregulation of cell cycle division associated 5 (CDCA5), and its protein product Sororin, a phosphorylation target and regulator of ERK and member of the cohesin complex, leading to G2/M phase arrest, sister-chromatid cohesion defects, impaired cell proliferation and tumor growth in mouse xenografts models. Here, we show that the loss of IWS1 results in genomic instability and accumulation of cytosolic dsDNA, an effect rescued by the expression of Sororin. The dsDNA is censored by cyclic GMP-AMP synthetase (cGAS), activating the STING/TBK1 pathway. The latter leads to increased expression of Interferon Regulatory Factor-3 (IRF-3) targets along with PD-L1. More importantly, IWS1 phosphorylation, U2AF2 RNA splicing pattern and Sororin expression negatively correlate with the cGAS/STING pathway and PD-L1 expression in lung adenocarcinoma patients. These results highlight the role of IWS1 phosphorylation-dependent RNA splicing in governing genomic stability, and proposes this axis as a novel drug target for a synergy with PD-L1/PD-1 blockade in lung adenocarcinoma patients.
Citation Format: Georgios I. Laliotis, Evangelia Chavdoula, Abdul Kaba, Alessandro La Ferlita, Vollter Anastas, Arturo Orlacchio, Lalit Sehgal, David P. Carbone, Vincenzo Coppola, Philip N. Tsichlis. The inhibition of IWS1 phosphorylation promotes genomic instability, the cGAS/STING pathway activation and PD-L1 levels, through the U2AF2 alternative RNA splicing and Sororin expression [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 PO010.
Abstract PO011: Systemic administration of Poly-ICLC promotes T cell tumor infiltration generating antitumor responses
Authors: Sultan Hussein , Wu Juan , Fesenkova Valentyna , Fan Aaron , Addis Diane , Salazar Andres , Celis Esteban 
Published: February 2021

Abstract
Background: Recent advances in immunotherapy have revolutionized cancer treatment. Immune checkpoint blockade and adoptive T cell therapy can induce durable responses in some patients. However, the majority of patients fail to respond. Absence of T cell infiltration to the tumor site in solid tumors is considered as one of the major obstacles for effective immunotherapy. Thus, strategies to enhance T cell trafficking and infiltration into the tumor parenchyma is a major research need.
Methods: Using a combination of in vivo mouse tumor models and in vitro assays we compared the capacity of various formulations and routes of administration of poly-IC (a dsRNA mimic that functions as a pattern recognition receptor ligand) in enhancing T cell tumor infiltration and generating antitumor responses.
Results: Our results showed that poly-ICLC (poly-IC containing poly-lysine and carboxymethylcellulose) enhanced CD8 T cell infiltration into the tumors resulting in the control of tumor growth. These effects relied both on the route of administration as well as on the formulation of poly-IC. Systemic administration (i.v. or i.m.) of poly-ICLC was significantly more effective in inducing CD8 T cell tumor infiltration as compared to intra-tumoral injections. Also, the effects poly-ICLC were substantially more pronounced as compared to unmodified poly-IC. The antitumor effect of poly-ICLC was mediated via MDA-5 and IFN-I, whereas TLR3 stimulation was not required. Interestingly, poly-ICLC stimulated IFN-I responses on tumor vascular endothelial cells (VECs) enhancing the expression of adhesion molecules (VCAM-I), production of IFN-I and T cell recruiting chemokines (CXCL9/CXCL10). Using conditional knockout mice, showed that ablation of IFNab receptors in VECs impaired the antitumor effects of poly-ICLC. IFN-I production upon MDA5 stimulation is required to enhance the secretion of (CXCL9/CXCL10) by VECs indicating that this IFN-I/CXCL9/CXCL10 regulatory axis is crucial for recruiting effector T cells into the tumor parenchyma. The T cell infiltrating effects of poly-ICLC were mainly observed in tumors and not in normal tissues.
Conclusions: Systemic administration of poly-ICLC improves T cell infiltration to solid tumors in an MDA5/IFN-I dependent manner. These findings should have a strong impact on improving T cell-based treatments for solid cancers such as adoptive T cell therapy and antitumor vaccines.
Citation Format: Hussein Sultan, Juan Wu, Valentyna Fesenkova, Aaron Fan, Diane Addis, Andres Salazar, Esteban Celis. Systemic administration of Poly-ICLC promotes T cell tumor infiltration generating antitumor responses [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 PO011.
Abstract PO012: A subset of monocyte-derived macrophages in glioblastoma multiforme supports antitumor immune responses
Authors: Kim Hyun-Jin 
Published: February 2021

Abstract
Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor and effective therapies are not well established. Lymphopenia and large infiltration of macrophages are major features of GBM. Although tumor-associated macrophages (TAMs) are known to suppress antitumor immune responses and support tumor growth and metastasis, recent studies reported that TAMs are a heterogeneous cell population, which includes both immune activating as well as immunosuppressive TAMs. However, because markers identifying these cells are not established, targeting TAMs is to induce antitumor immune responses is not yet an effective strategy. In this study, we identified a subset of macrophages that promote an anti-tumoral microenvironment in GBM. In single cell transcriptome analysis, we found that macrophages were divided to three populations based on their gene expression. One of these macrophage subsets expressed markers of monocyte-derived macrophages. These cells were a major source of pro-inflammatory chemokines among brain immune cells. In brain tumors without this monocyte-derived macrophage subpopulation, accumulation of CD4 and CD8 T cells and their cytokine production were diminished. Immuno-suppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and chemokines recruiting these cells were increased. Higher HIF-1α expression in tumors without these macrophages indicate that this subset might resolve hypoxia. Our finding suggests that this macrophage subset can support antitumor immune responses by suppressing a pro-tumoral microenvironment.
Citation Format: Hyun-Jin Kim. A subset of monocyte-derived macrophages in glioblastoma multiforme supports antitumor immune responses [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 PO012.
Abstract PO013: The mechanism of γδ T cell-mediated antitumor immunity in Glioblasotma multiforme
Authors: Park Jang Hyun , Lee Heung Kyu 
Published: February 2021

Abstract
Glioblastoma multiforme (GBM) is a highly malignant cancer with one of the highest mortality rates. The average survival is less than 2 years after diagnosis even with current therapies, which include chemotherapy and radiation. Furthermore, GBM has shown severe resistance to immunotherapies such as immune checkpoint blockade, which mainly target CD8 T cells. Recently, several studies showed that γδ T cells can be an alternative target of immunotherapy. Unlike conventional ab T cells, γδ T cells recognize stress-induced surface antigens such as NKG2D ligands and phosphoantigens. Because GBM cells highly express NKG2D ligands, γδ T cells could be good target for immunotherapy. However, a basic understanding of γδ T cell-mediated antitumor immunity is lacking. Using single-cell transcriptomic analysis, we analyzed the characteristics of GBM-infiltrating γδ T cells. Because γδ T cells were highly suppressed by the poorly oxygenated microenvironment of brain tumors, we inhibited tumor cell respiration using metformin, a drug used for type 2 diabetes, and found that this sufficiently reinvigorated γδ T cells. Reinvigorated γδ T cells had enhanced expression of NKG2D and multiple cytokines. In conclusion, this study highlights the importance of γδ T cells in GBM and the potential for new druggable pathways through reinvigoration of γδ T cells.
Citation Format: Jang Hyun Park, Heung Kyu Lee. The mechanism of γδ T cell-mediated antitumor immunity in Glioblasotma multiforme [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 PO013.
Abstract PO015: Tumor-cell-intrinsic epigenetic factors underlie the heterogeneity of immune infiltration and response to immunotherapy in pancreatic cancer
Authors: Li Jinyang , Yuan Salina , Norgard Robert J. , Yan Fangxue , Vonderheide Robert H. , Blanco Andres , Stanger Ben Z. 
Published: February 2021

Abstract
Resistance to immunotherapy is a major problem of current clinical care for cancer patients. While T cell abundance is essential for tumor responsiveness to immunotherapy, factors that dictate T cell infiltration in tumor microenvironments are not fully understood. To understand the tumor-cell-intrinsic factors underlying the heterogeneity of tumor immunity and sensitivity to immunotherapy, we established a new experimental system by generating a library of congenic pancreatic tumor cell clones from a genetic mouse model driven by mutant Kras and p53. These tumor cell clones robustly formed implanted tumors that recapitulated T-cell-inflamed and non-T-cell-inflamed tumor microenvironments, associated with distinct patterns of infiltration by T cells and myeloid cells. We found that the non-T-cell-inflamed phenotype was dominant over the T-cell-inflamed phenotype in the local tumor microenvironment. An integrated transcriptomic and epigenetic analysis revealed that tumor-cell-intrinsic expression of CXCL1, EPHA2, PTGS2, and USP22 as determinants of the non-T-cell-inflamed microenvironment, and ablation of tumor-cell-intrinsic CXCL1, EPHA2, PTGS2, or USP22 promoted T cell infiltration and sensitivity to a combination of chemotherapies, CD40 agonist, and checkpoint blockades. Furthermore, we performed an in vivo CRISPR-based genetic screen to identify tumor cell intrinsic epigenetic regulators of anti-tumor immunity and discovered novel therapeutic opportunities to improve the efficacy of currently developed immunotherapy for pancreatic cancer. These results demonstrated that heterogeneity of tumor immune phenotypes is driven by tumor-cell-intrinsic factors, including epigenetic factors, that can be manipulated to influence the outcome of immunotherapies.
Citation Format: Jinyang Li, Salina Yuan, Robert J. Norgard, Fangxue Yan, Robert H. Vonderheide, Andres Blanco, Ben Z. Stanger. Tumor-cell-intrinsic epigenetic factors underlie the heterogeneity of immune infiltration and response to immunotherapy in pancreatic cancer [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 PO015.
Abstract PO016: Single-cell analyses characterize circulating anti-tumor CD8 T cells and identify markers for their isolation
Authors: Pauken Kristen E. , Shahid Osmaan , Lagattuta Kaitlyn A. , Mahuron Kelly M. , Luber Jacob M. , Lowe Margaret M. , Huang Linglin , Delaney Conor , Long Jaclyn M. , Fung Megan E. , Newcomer Kathleen , Tsai Katy K. , Chow Melissa , Guinn Samantha , Kuchroo Juhi R. , Burke Kelly P. , Schenkel Jason M. , Rosenblum Michael D. , Daud Adil I. , Sharpe Arlene H. , Singer Meromit 
Published: February 2021

Abstract
The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA sequencing and T cell receptor (TCR) sequencing to detect and characterize “tumor matching” (TM) CD8+ T cells in the blood of mice with MC38 tumors and melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared to non-matching T cells in blood, and appeared less exhausted than matching counterparts in tumor. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome we identified candidate cell surface marker panels for TM cells in mice and melanoma patients, and validated markers in mice. Here, using combinations of markers provided better performance than single markers in identifying TM cells from non-TM cells in the blood. These data demonstrate that the TCR can be used to identify tumor-relevant populations for comprehensive characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells.
Citation Format: Kristen E. Pauken, Osmaan Shahid, Kaitlyn A. Lagattuta, Kelly M. Mahuron, Jacob M. Luber, Margaret M. Lowe, Linglin Huang, Conor Delaney, Jaclyn M. Long, Megan E. Fung, Kathleen Newcomer, Katy K. Tsai, Melissa Chow, Samantha Guinn, Juhi R. Kuchroo, Kelly P. Burke, Jason M. Schenkel, Michael D. Rosenblum, Adil I. Daud, Arlene H. Sharpe, Meromit Singer. Single-cell analyses characterize circulating anti-tumor CD8 T cells and identify markers for their isolation [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 PO016.