bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1893: The dynamics of T cell clonal repertoire under targeted therapy vs. immunotherapy in melanoma
Authors: Ding Lizhong , Campbell Katie M. , Medina Egmidio , Chen Kevin , Hugo Willy 
Published: July 2021

Abstract
Introduction. The current standard of care for metastatic melanoma patients utilizes either MAPK pathway inhibitors (MAPKi)-based targeted therapies or immune checkpoint inhibitors (ICI)-based immunotherapies. Almost every melanoma patient treated with MAPKi will relapse in a median of one year, whereas a small subset of ICI-treated melanoma patients experienced prolonged tumor control. Multiple reports have shown that both MAPKi and ICI treatment will induce increased T cell infiltration into the tumor. However, the T-cell receptor (TCR) clonotype dynamics across different therapies (MAPKi vs. ICI) and/or clinical response (responding vs. resistant) is still unknown. This study aims to compare the TCR repertoire dynamics and their associated tumor microenvironment (TME) phenotypes in melanoma pre- vs. post-ICI or MAPKi to see if there are unique patterns associated with better tumor control.
Methods. Publicly available bulk RNA-seq data of 345 melanoma samples pre- and post- treatment were downloaded, including two MAPKi (n=116 tumors) and two ICI data sets (n = 229 tumors). All samples were classified into three groups: pre-treatment (PT), on-treatment responding (OT-R), and on-treatment non-responding (OT-NR). T cell clonotype and gene expression were quantified from the RNA-seq data using trust4 and HISAT2/htseq-count, respectively. Although the transcripts of T cells are mixed with tumor cells in the bulk RNA-seq data, the TCR clonotype abundance showed significant correlation with T cell marker expression, offering a measure of robustness in the identification of TCR from bulk tumor derived RNA-seq data.
Results. Both MAPKi and ICI therapies significantly increase the TCR count, abundance, diversity, and clonality in OT-R samples compared to PT and OT-NR samples. Intriguingly, we observed significantly higher clonal replacement of PT samples' T cell clonotypes with novel, OT-specific clonotypes under both therapies. Of note, in the tumor subset that responded to the ICI, the increase of these novel TCR were significantly associated with the enrichment of naïve/memory CD4 and CD8 T cell signatures.
Conclusions. In melanoma, intratumoral TCR dynamics patterns in response to MAPKi and ICI are mostly similar, except for the upregulation of naïve/memory T cell signatures in the subset of ICI-responder tumors. These insights may eventually lead to better markers for therapy-induced, productive anti-tumor immunity in melanoma.
Citation Format: Lizhong Ding, Katie M. Campbell, Egmidio Medina, Kevin Chen, Willy Hugo. The dynamics of T cell clonal repertoire under targeted therapy vs. immunotherapy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1893.
Abstract 1895: caAtlas: An immunopeptidome atlas of human cancer
Authors: Yi Xinpei , Liao Yuxing , Wen Bo , Li Kai , Dou Yongchao , Savage Sara R. , Zhang Bing 
Published: July 2021

Abstract
At the core of immunotherapy is the T cell recognition of tumor antigens. Thus, comprehensive characterization of tumor antigens is essential for the design of effective and safe cancer immunotherapy strategies. Mass spectrometry (MS)-based immunopeptidomics allows high-throughput, direct identification of major histocompatibility complex (MHC)-bound peptides in vivo. Here, we collected 42 published human immunopeptidomic datasets, which include 327 cancer samples covering nine cancer types and 216 non-cancerous samples. A systematic, quality-controlled analysis of all 51.6 million MS/MS spectra using an open search algorithm identified 364,283 peptides, including 11,647 modified peptides associated with 80 types of modifications. Unmodified peptides showed high levels of predicted binding affinities by NetMHCpan; however, the predicted binding affinities for the modified peptides were much lower, suggesting a deficiency of existing computational tools in making predictions for modified peptides. Analysis of the 416 phosphorylated and 1,239 acetylated HLA class I peptides revealed distinct sequence motifs, and the pattern for the phosphopeptides was consistent with previous reports. Further interrogation of all identified peptides revealed evidence for tumor specific-presentation of hundreds of known and novel cancer-testis antigens as well as tumor associated antigens. We also found non-tumor-specific presentation of 44 previously annotated cancer-testis antigens. Applying NeoQuery, a newly developed computational pipeline, to our dataset identified immunopeptidomic evidence for more than 1,000 somatic mutation-derived neoantigens, and a subset of them were further validated through a traditional MS/MS peptide identification pipeline. We make all these data together with annotated MS/MS spectra supporting each individual antigen identification in a publicly accessible, easily browsable web portal named cancer antigen atlas (caAtlas, http://www.zhang-lab.org/caatlas/). caAtlas provides a fundamental resource for the selection and prioritization of MHC-bound peptides for immunogenicity testing and cancer immunotherapy development.
Citation Format: Xinpei Yi, Yuxing Liao, Bo Wen, Kai Li, Yongchao Dou, Sara R. Savage, Bing Zhang. caAtlas: An immunopeptidome atlas of human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1895.
Abstract 1899: Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting
Authors: Bear Adham S. , Blanchard Tatiana , O'Hara Mark H. , Scholler John , Vonderheide Robert H. , Linette Gerald P. , Carreno Beatriz M. 
Published: July 2021

Abstract
Activating missense mutations within RAS oncogenes are among the most prevalent genomic alterations observed in human cancers and drive oncogenesis in the three most lethal tumor types. Emerging evidence suggests mutant KRAS (mKRAS) may be targeted immunologically, but mKRAS epitopes remain poorly defined. Here, we employ multi-omic approaches to characterize optimal HLA class I-restricted mKRAS epitopes. Using in silico epitope prediction, we identify candidate mKRAS G12 epitopes with high predicted binding affinity to prevalent HLA class I alleles. We utilize biochemical approaches to identify mKRAS epitopes with high measured binding affinity and stability to HLA-A*03:01, -A*11:01 and -B*07:02. Furthermore, we provide proteomic validation of epitope processing and presentation by these alleles. We report mKRAS G12V and G12R epitopes are immunogenic as evidenced by the isolation of mKRAS G12V- and G12R-specific TCRαβ from healthy donors. The transfer of mKRAS-TCRs to primary CD8+ T cells serves as sensitive probes to validate mKRAS epitope processing and presentation by tumor cells and confers cytotoxicity against mKRAS human tumor cell lines of various histologies. The kinetics of lytic activity correlate with measured TCR avidity and mKRAS/HLA class I complex abundance expressed on the tumor cell surface. Finally, the adoptive transfer of mKRAS-TCR engineered primary CD8+ T cells to NOD scid gamma mice leads to tumor eradication in an orthotopic mKRAS lung cancer model. This study validates mKRAS as a bona fide tumor neoantigen and supports strategies to identify recurrent driver alterations for immunological targeting. Based on this work, clinical studies targeting mKRAS in cancer patients using vaccines and adoptive T cell therapy are under active investigation.
Citation Format: Adham S. Bear, Tatiana Blanchard, Mark H. O'Hara, John Scholler, Robert H. Vonderheide, Gerald P. Linette, Beatriz M. Carreno. Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1899.
Abstract 1907: Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumor immunity
Authors: Papp Benjamin Tamas , Manczinger Máté , Balogh Gergő , Koncz Balázs , Asztalos Leó , Kemény Lajos , Papp Balázs , Pál Csaba 
Published: July 2021

Abstract
The human leukocyte antigen class I (HLA-I) genes shape our immune response against pathogens and cancer. Certain HLA-I variants can bind a much wider range of peptides than others, a feature that could be favorable against a range of viral diseases. However, the implications of this phenomenon on cancer immune response is unknown. In this paper, we quantified peptide repertoire breadth (or promiscuity) of a representative set of HLA-I alleles, and found that cancer patients that carry HLA-I alleles with high peptide binding promiscuity are characterized by significantly worse prognosis after immune checkpoint inhibitor treatment. This trend can be explained by a reduced capacity of promiscuous HLA-I molecules to discriminate between human self and tumor peptides, yielding a shift in regulation of T-cells in the tumor microenvironment from activation to tolerance. In summary, HLA-I peptide binding specificity shapes neopeptide immunogenicity and the self-immunopeptidome repertoire in an antagonistic manner. It could also underlie a negative trade-off between antitumour immunity and the genetic susceptibility to viral infections.
Citation Format: Benjamin Tamas Papp, Máté Manczinger, Gergő Balogh, Balázs Koncz, Leó Asztalos, Lajos Kemény, Balázs Papp, Csaba Pál. Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1907.
Abstract 1930: 4-nitroquinoline-1-oxide enhances induction of apoptosis preferentially in HPV positive head and neck squamous cell carcinoma cells
Authors: Shishodia Gauri , Lee Alice , Toledo Rhodee Ric , Zimmerman Emily , Rong Xiaohua , Xiao Adam , Harrison Lynn , Nathan Cherie Ann 
Published: July 2021

Abstract
Background: Tobacco use and human papillomavirus (HPV) infection are both strong contributors to the oncogenesis of head and neck squamous cell carcinoma (HNSCC). Despite HPV's causative role in HNSCC, it confers no statistically significant difference in mutational profile between HPV-associated HNSCC smokers and non-smokers. Our earlier preliminary data suggested that HPV positive (+) HNSCC cells have better activation of DNA repair proteins compared to HPV negative (-) HNSCC cells when treated with 4NQO, a mutagen and carcinogen which serves as a surrogate for tobacco exposure. This may partially explain HPV+ HNSCC's higher mutational resistance. In addition to increased DNA repair, HPV+ cells may also eliminate mutations through higher rates of apoptosis compared to HPV- cells. Hence, we wanted to test this hypothesis by analyzing the effects of 4NQO on apoptosis in HPV+ and HPV- HNSCC cells.
Methods: NOK, NOK E6.E7, SCC40 (HPV-), SCC104 and UMSCC47 (HPV+) cells were treated with different concentrations of 4NQO (0, 0.1, and 0.2 ug/ml) for 24 and 48 hours. Untreated (control) and 4NQO treated cells were assessed for cell viability using MTT assay. Apoptotic cells were determined using Annexin-V FITC flow cytometry analysis, and Western blot was performed to check the apoptotic proteins for the afore-mentioned control and 4NQO treatments.
Results: MTT assay showed decreased cell viability of NOK E6.E7, SCC47 and SCC104 cells in response to 4NQO treatment compared to relatively higher cell viability of SCC40 cells. Flow cytometry confirmed that HPV+ HNSCC cells are relatively more apoptotic compared to HPV- cells following 4NQO treatment at 24 and 48 hours. This is further supported by activation of pro-apoptotic proteins including p53, cleaved caspase 3, cleaved PARP, cleaved caspase 9, and p21 to a greater extent in HPV+ cells at different time points of 4NQO treatment using Western blot analysis.
Conclusion: Our in-vitro data suggest HPV may stimulate a protective measure against smoking-induced mutations by increasing apoptosis before cells can contribute to the HNSCC mutational profile. Taken together, these data explain why HPV associated HNSCC have a better prognosis than HPV negative irrespective of smoking history.
Citation Format: Gauri Shishodia, Alice Lee, Rhodee Ric Toledo, Emily Zimmerman, Xiaohua Rong, Adam Xiao, Lynn Harrison, Cherie Ann Nathan. 4-nitroquinoline-1-oxide enhances induction of apoptosis preferentially in HPV positive head and neck squamous cell carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1930.
Abstract 1932: Talazoparib interacts with oncolytic reovirus to enhance death-inducing signaling complex (DISC)-mediated apoptosis and immune response
Authors: Kyula Joan N. , Roulstone Victoria , Elliott Richard , Whittock Harriet , Bozhanova Galabina , McLaughlin Martin , Pedersen Malin , Krastev Dragomir , Pettitt Stephen , Legrand Arnaud , Tenev Tencho , Wright James , Yu Lu , Choudhary Jyoti , Meier Pascal , Lord Christopher J. , Melcher Alan , Wilkinson Grey , Coffey Matt , Harrington Kevin J. 
Published: July 2021

Abstract
Reovirus (RT3D) is a naturally occurring double-stranded RNA oncolytic virus that has shown preclinical efficacy in a wide range of tumor types. Early phase clinical studies have shown that this agent has modest monotherapy efficacy and can safely be combined with cytotoxic chemotherapy regimens. In the current studies, we used a high-throughput drug screen approach of different targeted therapeutic agents with the aim of looking for potential viral sensitizers that could enhance RT3D tumor killing. BMN-673 (talazoparib), a clinically approved poly(ADP)-ribose polymerase 1 (PARP-1) inhibitor was identified as a top hit and found to sensitize profoundly to RT3D both in vitro and in vivo in human xenograft tumors in a nude mouse model. We found that RT3D activated cellular PARP1 and was associated with PARylation of cellular proteins, including components of the DISC-associated cell death machinery. Combined treatment with RT3D and talazoparib enhanced extrinsic apoptosis (amplified by autocrine/paracrine TNF-α and TRAIL signaling), NF-κB pathway activity and pro-inflammatory cytokine production (CCL5/RANTES, CXCL8/IL8, CXCL1/GRO and CXCL10/IP10). Signaling was shown to be dependent on nucleic acid sensing mechanisms mediated by RIG-I and TLR3. We also found anti-tumour efficacy in an immunocompetent mouse model and this correlated with an increase in an immune response following combination treatment of RT3D and talazoparib. Our data provide a strong rationale for the combination of oncolytic RT3D with PARP1 inhibitors to exploit immunogenic response in cancer treatment.
Citation Format: Joan N. Kyula, Victoria Roulstone, Richard Elliott, Harriet Whittock, Galabina Bozhanova, Martin McLaughlin, Malin Pedersen, Dragomir Krastev, Stephen Pettitt, Arnaud Legrand, Tencho Tenev, James Wright, Lu Yu, Jyoti Choudhary, Pascal Meier, Christopher J. Lord, Alan Melcher, Grey Wilkinson, Matt Coffey, Kevin J. Harrington. Talazoparib interacts with oncolytic reovirus to enhance death-inducing signaling complex (DISC)-mediated apoptosis and immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1932.
Abstract 1950: A ubiquitination cascade regulates the integrated stress response and epithelial cancer survival
Authors: Cervia Lisa D. , Shibue Tsukasa , Gaeta Benjamin , Borah Ashir , Leung Lisa , Li Naomi , Dumont Nancy , Gonzalez Alfredo , Bick Nolan , Kazachkova Mariya , Dempster Joshua , Krill-Burger John M. , Udeshi Namrata , Olive Meagan , Carr Steven A. , Root David E. , Piccioni Federica , McFarland James M. , Vazquez Francisca , Hahn William C. 
Published: July 2021

Abstract
Systematic identification of signaling pathways required for the viability of cancer cells will facilitate the development of novel cancer therapies. We used gene essentiality measurements in 726 cancer cell lines to identify selective co-essentiality modules and found a functional ubiquitination cascade containing UBA6, BIRC6, KCMF1 and UBR4, which encode an E1, E2, and two heterodimeric E3 subunits, respectively, as a vulnerability in a subset of epithelial tumors. Suppressing BIRC6 in cancer cell lines that are dependent on this ubiquitination cascade led to a strong reduction in cell fitness in vitro, and to potent tumor regression and metastasis suppression in vivo. Mechanistically, BIRC6 suppression resulted in selective and robust activation of the integrated stress response (ISR) signaling via upregulation of the heme-regulated inhibitor (HRI). Using proteomic profiling, we found that HRI itself is a key degradation target of the UBA6/BIRC6/KCMF1/UBR4 cascade. These observations demonstrate a protein ubiquitination cascade regulating ISR and highlight the potential of this cascade as a novel therapeutic target for a subset of epithelial cancers.
Citation Format: Lisa D. Cervia, Tsukasa Shibue, Benjamin Gaeta, Ashir Borah, Lisa Leung, Naomi Li, Nancy Dumont, Alfredo Gonzalez, Nolan Bick, Mariya Kazachkova, Joshua Dempster, John M. Krill-Burger, Namrata Udeshi, Meagan Olive, Steven A. Carr, David E. Root, Federica Piccioni, James M. McFarland, Francisca Vazquez, William C. Hahn. A ubiquitination cascade regulates the integrated stress response and epithelial cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1950.
Abstract 1954: Identifying synthetic lethality with novel CDK2 small molecule inhibitors via integration of high-content microscopy and -omics level platforms
Authors: Wang Tim Sen , Almaden Jon , Shen Chen , Lapek John , Niessen Sherry , Miller Nichol , Dann Stephen , VanArsdale Todd 
Published: July 2021

Abstract
CDK4/6 small molecule inhibitors represent a milestone in treating hormone receptor-positive breast cancer. PALOMA (Palbociclib: Ongoing Trials in the Management of Breast Cancer) studies have confirmed prolonged progression-free survival after CDK4/6 inhibitor and anti-estrogen therapy. Notably, disease progression is observed in a subset of patients receiving Palbociclib-Fulvestrant treatment (Turner et al., NEJM 2018). Circulating tumor DNA from PALOMA-3 patients revealed genetic mutations correlating with patient response (O'Leary et al., Cancer Discov, 2018). Compensations in CDK4/6i resistance include circumvention of CDK4/6 substrate regulation, CCNE1/2 amplification (Herrera-Abreu et al., Cancer Res. 2016), and compensatory CDK2 activity. The importance of compensatory CDK2 cancer re-wiring is highlighted by recently reported, highly efficacious CDK2/4/6i (Freeman-Cook et al., in review). Thus, mechanistic understanding of cancer cell and compensatory CDK2 activity is imperative to improve patient outcome. Acute, temporal phenotypes in CDK2-signaling have been observed by live single-cell tracking microscopy in human breast epithelial and ER+ breast cancer cells (Arora & Moser et al., in review). In extending these studies, we utilize first-in-class small molecule inhibitors against CDK2 combined with high content imaging approaches to illuminate cancer cell CDK2 signaling and identify potential synthetic lethality. We report biomarkers parsed in cycling populations as quantifiable phenotypes and identify disengaged control of several processes including S- and G2/M licensing after CDK2i. Combined with internal -omics studies, CDK2i selective molecules support a positive regulatory role of CDK2 on CCNB1-PLK1 signaling before mitotic entry. We combine our high-content techniques with proximity labeling to quantify alternative CDK-Cyclin complex formation following pharmacologic perturbation. We hypothesize that dysregulated CDK-Cyclin complex formation elicits unintended CDK2 kinase activity, revealing potential synthetic lethality with inhibition of centrosome duplication pathways in ER+ breast cancers.
Citation Format: Tim Sen Wang, Jon Almaden, Chen Shen, John Lapek, Sherry Niessen, Nichol Miller, Stephen Dann, Todd VanArsdale. Identifying synthetic lethality with novel CDK2 small molecule inhibitors via integration of high-content microscopy and -omics level platforms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1954.
Abstract 1961: Cyclin-dependent kinase inhibition in mesothelioma
Authors: Kratzke Marian , Kren Betsy , Porter Stephen , Scaria George , Klein Mark A. 
Published: July 2021

Abstract
Background: Mesothelioma is a cancer that arises out of the pleura or the peritoneum and is considered incurable in the majority of patients afflicted. Abnormalities of the cell cycle pathway are among the most common molecular alterations in mesothelioma. Previously, we have demonstrated that inhibition of CDK4/6 by abemaciclib or palbociclib is effective against mesothelioma in vitro. Increased expression of Cyclin E has been demonstrated to be one mechanism of resistance to CDK4/6 inhibition in other cancers. We hypothesized that select cell cycle-related proteins may compensate for inhibition of one part of the cell cycle machinery and that the CDK2 inhibitor dinaciclib may act synergistically in combination with abemaciclib.
Methods: Dinaciclib was evaluated for activity against mesothelioma cells in vitro with regard to cell proliferation and colony formation. In addition, dinaciclib was evaluated in combination with abemaciclib at several concentration combinations in a cell proliferation assay to determine if the combination may be additive or synergistic. Combination indices (CI) were calculated via the Chou-Talalay method. Immunoblotting was used to evaluate for expression of key survival proteins after treatment with abemaciclib.
Results: The IC50 of dinaciclib was determined to be 18 nM, 23 nM, 32 nM, and 33 nM in mesothelioma cell lines H2373, H2052, H2452, and H2461, respectively. Colony formation was decreased significantly after 72 hours incubation with 50 nM or 100 nM dinaciclib in Bap1-expressing (35.1 ± 2%; 22.8 ± 2%) and Bap1-null cell lines (14.5 ± 3%; 8.1 ± 2%) versus untreated controls. CI &lt; 1 (denoting synergism) was identified for several combinations of varied concentrations of abemaciclib and dinaciclib for both cell lines evaluated. Further, treatment with abemaciclib for 72 hrs in both Bap1-expressing and Bap 1-null cells at 1x the IC50 resulted in complete loss of FoxM1 expression and pro-survival survivin and significantly decreased the expression of Mcl-1 and XIAP.
Conclusions: Dinaciclib is a potent inhibitor of mesothelioma cell growth. The combination of abemaciclib and dinaciclib is synergistic across a spectrum of concentrations in vitro. Further experiments are currently underway to determine which CDKs and related proteins may be more effectively targeted in mesothelioma. As the cell cycle is altered in the vast majority of mesothelioma tumors, select combinations of CDK inhibition may be a feasible future therapeutic strategy against mesothelioma.
Citation Format: Marian Kratzke, Betsy Kren, Stephen Porter, George Scaria, Mark A. Klein. Cyclin-dependent kinase inhibition in mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1961.