bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6062: Radiosensitizing head and neck squamous cell carcinoma using isothiocyanates
Authors: Wicker Christina Ann , Thompson Samuel , Dubey Poornima , Takiar Vinita 
Published: June 2022

Abstract
Head and neck cancer kills over 400,000 people each year with the majority of cases being head and neck squamous cell carcinoma (HNSCC). Despite major advances in cancer treatment, radiation resistance contributes to increased morbidity and mortality of patients with HNSCC. Few FDA-approved radiosensitizers exist for the treatment of HNSCC and the majority are associated with severe adverse effects. Therefore, there is a clear need to examine novel treatment combinations to improve radiosensitivity and HNSCC outcomes. Isothiocyanates enhance response to cytokines, chemotherapy, and radiation in other in vitro and in vivo cancer models, including pancreatic and breast cancer. Isothiocyanates are antioxidants found in cruciferous vegetables such as watercress and broccoli. Phenethyl isothiocyanate (PEITC) was well tolerated by patients in chemopreventative clinical trials and was thus selected for this study. We hypothesize that PEITC radiosensitizes HNSCC cells through increasing DNA damage, apoptosis and reactive oxygen species (ROS). Non-human papilloma virus or P16 negative HNSCC are associated with increased radioresistance and as such human HNSCC cell lines HN5 and CAL27 were selected. Combination of PEITC and photon radiation (XRT) decreased cell survival by half as compared to cells treated with PEITC or XRT alone for both HN5 and CAL27 cells as determined by clonogenic assay (n≥3). PEITC enhanced XRT-induced apoptosis in HN5 and CAL27 cells as indicated by increased cleavage of effector caspases 3 and 7, which was reversed upon treatment with pan-caspase inhibitor, QVD-OPH. Preliminary comet assays identified that combination of PEITC with XRT significantly increased Tail DNA % relative to vehicle (p&lt;0.001), PEITC alone (p&lt;0.0001), or XRT alone (p&lt;0.0001) in HN5 cells. Preliminary data in CAL27 cells identified significantly increased signal of y-H2Ax in cells treated with both PEITC and XRT was 2.2 fold higher than XRT alone (p&lt;0.001) and 12.1 fold higher than PEITC alone (p&lt;0.001) in CAL27 cells. PEITC increased XRT-induced ROS generation in CAL27 cells relative to independent treatment as determined by 2′,7′ dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Taken together, these results support that PEITC synergistically enhances HNSCC cell response to XRT. The results of this study warrant further investigation into the potential of PEITC to improve radiation efficacy in pre-clinical HNSCC models with the long-term goal of testing this well-tolerated compound in clinical trials.
Citation Format: Christina Ann Wicker, Samuel Thompson, Poornima Dubey, Vinita Takiar. Radiosensitizing head and neck squamous cell carcinoma using isothiocyanates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6062.
Abstract 6079: Spatial deconvolution from bulk DNA methylation profiles determines intratumoral epigenetic heterogeneity
Authors: Xie Yumo , Zhang Yu , Tang Guannan , Wang Xiaolin , Huang Meijin , Luo Yanxin , Yu Huichuan 
Published: June 2022

Abstract
Purpose: Intratumoral heterogeneity emerges from accumulating genetic and epigenetic changes during tumorigenesis, which may contribute to therapeutic failure and drug resistance. We aimed to develop a tool that can evaluate the intratumoral epigenetic heterogeneity using the DNA methylation profiles from bulk tumors.
Methods: Ggenomic DNA of three laser micro-dissected tumor regions, including digestive tract surface (DTS), central bulk (CB), and invasive margin (IM), was extracted from formalin-fixed paraffin-embedded (FFPE) sections of 98 colorectal cancer patients. The genome-wide methylation profiles were generated with methylation array. The most variable methylated probes were selected to construct a DNA methylation-based heterogeneity (MeHEG) estimation tool that can deconvolve the proportion of each reference tumor region with the support vector machine model-based method. A PCR-based assay for quantitative analysis of DNA methylation (QASM) was developed to specifically determine the methylation status of each CpG in MeHEG assay at single-base resolution to realize fast evaluation of epigenetic heterogeneity.
Results: In the discovery set with 79 patients, the differentially methylated CpGs among the three tumor regions were found. The 7 most representative CpGs were identified by random forest analysis and subsequently selected to develop the MeHEG algorithm. We validated its performance of deconvolution of tumor regions in an independent cohort with 19 patients. In addition, we showed the significant association of MeHEG-based epigenetic heterogeneity with the genomic heterogeneity in mutation and copy number variation in our in-house and TCGA cohorts. Finally, we found that the patients with higher MeHEG score had worse disease-free and overall survival outcomes.
Conclusion: By constructing a 7-loci panel with a machine learning approach and QASM assay to facilitate its use in a PCR manner, we developed a valuable method to evaluate the intratumoral epigenetic heterogeneity. The MeHEG algorithm provides innovative insights into the intratumoral heterogeneity from the epigenetic perspective that may add valuable sources to current knowledge about tumor heterogeneity.
Citation Format: Yumo Xie, Yu Zhang, Guannan Tang, Xiaolin Wang, Meijin Huang, Yanxin Luo, Huichuan Yu. Spatial deconvolution from bulk DNA methylation profiles determines intratumoral epigenetic heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6079.
Abstract 6110: Immune cell infiltrative characteristics reveals the superior efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in a real-world cohort of resectable non-small cell lung cancer
Authors: Cai Wenhan , Jing Miao , Wen Jiaxin , Gu Yajun , Zhao Xiaochen , Xue Zhiqiang 
Published: June 2022

Abstract
We aimed to analyze the efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in the real-world settings, and to further explore tumor immune microenviroment (TIME), as well as its influence on response of neoadjuvant therapy in patients with NSCLC. Fifty-three patients with neoadjuvant therapy (immunochemotherapy, n=22; chemotherapy alone, n=31), resectable stage I~III, age≥18 years, and ECOG performance status 0-1 were recruited in the study. Fluorescent multiplex immunohistochemistry was performed by the automated quantitative pathology imaging system with tumor samples obtained in radical surgery. The major pathologic response (MPR) rate was significantly higher in patients with neoadjuvant immunochemotherapy than chemotherapy alone (p=.025; OR=4.222, 95% CI: 1.292~13.800). Patients received immunochemotherapy had higher pathologic complete response (pCR) rate than those with chemotherapy (p=.168; OR=3.150, 95% CI: 0.792~12.535). Compared with chemo alone, the tumor to stroma ratio of CD68+CD163- density was significantly elevated in patients subjected to immunochemotherapy (p=.0399). When patients were stratified by the pathologic response to neoadjuvant immunochemotherapy, the CD56dim in stroma significantly increased in patients achieved pCR than non-pCR (p=.038). The density of CD3+CD4+ cells (stroma, p=.039; total, p=.027) and CD20+ (total, p=.027) immune cells was significantly higher in patients achieved MPR than non-MPR. In patients administered with neoadjuvant chemotherapy alone, the expression level of PD-1 (p=.036), the density of FoxP3+ (stroma, p=.025; total, p=.013) and CD3+CD4+FoxP3+ (total, p=.042) cells significantly reduced in patients reached pCR. The density of CD20+ cells in stroma (p=.034) and the number of tertiary lymphoid structures (TLS; p=.006) were significantly higher in patients reached MPR. In conclusion, the therapeutic efficacy was improved by neoadjuvant immunochemotherapy in patients with NSCLC, which may be associated with the TIME remodeling, especially the migration of M1 macrophage from stroma to tumor islet. Clusters of NK, Th, Treg and B, PD-1, and TLS also play important role in response to neoadjuvant therapy.
This work was supported by National Natural Science Foundation of China (NO. 62076254)
Citation Format: Wenhan Cai, Miao Jing, Jiaxin Wen, Yajun Gu, Xiaochen Zhao, Zhiqiang Xue. Immune cell infiltrative characteristics reveals the superior efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in a real-world cohort of resectable non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6110.
Abstract 6114: Prognostic value of the tumor-infiltrating lymphocytes in Miller-Payne grade 4 triple-negative breast cancer following neoadjuvant chemotherapy
Authors: Ma Jianli , Deng Yuwei , Chen Dawei , Li Xiaomei , Yu Zhiyong , Wang Haibo , Zhong Lei , Li Yingjie , Wang Chengqin , Zhou Xiaoping , Li Xiang , Zhang Qingyuan , Yu Jinming 
Published: June 2022

Abstract
Background Triple-negative breast cancer (TNBC) with pathological complete response after neoadjuvant chemotherapy (NACT) has better prognosis, but there remain uncertainties upon the prognostic judgement for Miller-Payne 4 patients. We evaluated the prognostic correlations with the tumor-infiltrating lymphocytes (TILs) status in Miller-Payne 4 patients.
Methods A total of 272 TNBC patients with NACT were assessed as Miller-Payne grade 4/5. Pre-treatment core biopsies from Miller-Payne 4 patients were specifically assessed for TILs with prognostic relevance using standardized methods. The corresponding spatial distributions and components of the TILs were thoroughly analyzed by IMC and proteomic.
Results The 5-year disease-free survival (DFS) was 63.8% for Miller-Payne 4 and 83.0% for Miller-Payne 5 (p=0.003), and overall survival (OS) was 71.0% and 85.5% respectively (p=0.007). High TILs were significantly associated with longer DFS (p=0.007) and OS (p=0.004) in Miller-Payne 4/5 patients, and also in the Miller-Payne 4 subgroup (both p=0.016). Spatially, Miller-Payne 4 with good prognosis had an inflamed signature, included dominant T cells surrounding tumor cells with focal infiltrations, limited scattered myeloid-derived cells which were separated from T cells, and reduced suppressive cytokines. Functionally, 109 immunologically effective proteins were upregulated and 76 immunosuppressive components were downregulated, indicating more immunological effective activities. By contrast, Miller-Payne 4 with poor prognosis had an excluded signature. We also observed similar immune signatures in Miller-Payne 5.
Conclusion Miller-Payne 4 combined with immunotyping of the TILs could be powerful prognostic indicators for Miller-Payne 4 TNBC with NACT.
Citation Format: Jianli Ma, Yuwei Deng, Dawei Chen, Xiaomei Li, Zhiyong Yu, Haibo Wang, Lei Zhong, Yingjie Li, Chengqin Wang, Xiaoping Zhou, Xiang Li, Qingyuan Zhang, Jinming Yu. Prognostic value of the tumor-infiltrating lymphocytes in Miller-Payne grade 4 triple-negative breast cancer following neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6114.
Abstract 6121: Correlation of tumor immune microenvironment status and driver genes alterations in Chinese non-small-cell lung cancer patients
Authors: Guo Jindong , Xiong Liwen , Yuan Haibin , Hu Mengna , Zhang Bei , Zhang Ding 
Published: June 2022

Abstract
Background: Patients with different driver genes show a variety of immunotherapy efficacy for non-small-cell lung cancer (NSCLC). In addition to PD-L1, the evaluation of the immune microenvironment contributes to a deeper understanding of the mechanisms of immunotherapy resistance.
Methods: Tumor tissues from 2674 NSCLC patients were collected. Genetic alterations were profiled using targeted next-generation sequencing with 733 cancer-related genes panel. Immunohistochemistry was used to evaluate the PD-L1 tumor proportion score, (TPS) expression on the surface of tumor cells. Tumor-infiltrating immune cells of 120 tumor samples were labeled with multiple immunofluorescence staining.
Results: Overall, CD8+ T cell infiltration level was negatively associated with both EGFR copy number gain (CNG, p &lt; 0.001) and ERBB2 CNG (p = 0.021). Also, the presence of EGFR or ERBB2 CNG was related with fewer natural killer cell infiltration (EGFR: p &lt; 0.001; ERBB2: p = 0.036) and a lower M1/M2 tumor-associated macrophages ratio compared to wild-type tumors (EGFR: p = 0.051; ERBB2: p = 0.036), suggesting a relatively weaker anti-tumor ability. In addition, we noted that KRAS CNV was negatively related to M2 macrophages (p = 0.027). Patients carrying ALK translocation (p &lt; 0.001), ROS1 translocation (p = 0.006), KRAS mutations (p &lt; 0.001) and MET (p &lt; 0.001) mutations had the elevated PD-L1 TPS expressions, while those harboring EGFR (p &lt; 0.001) and ERBB2 mutations (p = 0.001) had lower PD-L1 expression. Compared to the other EGFR mutations, PD-L1 expression in EGFR CNG tumors was higher, and no significant differences were found between CNG and other types of mutation in patients harboring ERBB2, KRAS, MET alterations.
Conclusion: NSCLC patients with EGFR CNG and ERBB2 CNG had fewer invasion of cytotoxic T cells and NK cells and a lower M1/M2 macrophages ratio. EGFR CNG may intensively modify the tumor immune microenvironment, which is a possible mechanism contributing to EGFR-TKI resistance.
Citation Format: Jindong Guo, Liwen Xiong, Haibin Yuan, Mengna Hu, Bei Zhang, Ding Zhang. Correlation of tumor immune microenvironment status and driver genes alterations in Chinese non-small-cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6121.
Abstract 6182: A comprehensive panel of reporter cell lines to accelerate immune-checkpoint antibody discovery
Authors: Wang Guoqian , Guo Zhengcheng , Chen Hongling , Liu Chang , Ning Jinying , Hao Feng 
Published: June 2022

Abstract
Anti-tumor immune therapy has achieved great success. Antibody drugs targeting PD1/PD-L1 have brought significant benefits for cancer patients. In the post-PD1/PD-L1 era, many novel targets for tumor-related immune modulation have been discovered, and tremendous efforts have been put to develop new biologics for these targets. There is an urgent need for a high-throughput functional system that mimics tumor immune microenvironment to screen antibodies. Equipped with expertise in tumor immunology and cell biology, KYinno has generated a panel of reporter cell lines to accelerate immune-checkpoint antibody discovery. The reporter system includes two types of engineered cell lines, one is CHO-K1 or 293T based aAPC (artificial antigen presenting cell) which provides both stimuli and inhibitor (ligand) signals, and the other one is Jurkat-NFAT-luciferase reporter cell line that over-expresses the drug target (receptor). In this co-culture system, the ligand-receptor complex can induce NFAT inhibitory signals. The functional antibodies can rescue the inhibitory signal by blockage of the ligand-receptor interaction. All the reporter cell lines have been well validated with benchmark antibodies. Currently, the systems cover immune modulation for TIGIT, LILRB1, LILRB2, PVRIG, Lag3, TIM3, NKG2a, NKp30, PD1, NKp46, etc.
Citation Format: Guoqian Wang, Zhengcheng Guo, Hongling Chen, Chang Liu, Jinying Ning, Feng Hao. A comprehensive panel of reporter cell lines to accelerate immune-checkpoint antibody discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6182.
Abstract 6189: Development of an anti hepatocellular carcinoma CAR T strategy targeting PDL1
Authors: Lee Kyung-Sik , Park Hye-Seong , Park Guk-Yeol , Lee Gi-Chan , Choi Eun-Ji , Yu Jae-in , Yang Seung-Joo , Kim Mihwa , Choi Yoonjoo , Lee Je-Jung , Rhee Joon Haeng , Park Bum Chan , Park Jae Eun 
Published: June 2022

Abstract
[Purpose] Immunosuppressive tumor microenvironment (TME) is the major hurdle to cancer immunotherapy. Advanced hepatocellular carcinoma (aHCC) is one of the representative cold tumors with immunosuppressive TME and presents obvious correlation between immune check point expression, such as programmed cell death ligand 1 (PD-L1), and poorer prognosis. In aHCC patients, cancer cells and stellate cells in TME appeared to express high level of PD-L1, which should suppress activities of antitumor immune cells. In this context, the combination of PD-1/PD-L1 inhibitors and other therapeutic modalities are tried to treat aHCC. The chimeric antigen receptor (CAR) T cell therapy is a potent way of eradicating cells expressing targetable antigens. Removal of PD-L1 expressing cells in the aHCC TME will improve the clinical outcomes of current therapies against aHCC. In the present study, we developed an autologous anti-PD-L1 CAR T strategy and show high efficacy of tumor suppression using an HCC xenograft model.
[Result] We constructed second generation CAR lentiviral vector expressing an unique anti-PD-L1 scFv manifesting moderated affinity. The scFv was specifically generated by phage display technique using human B cell-derived naïve cDNA library, which targets PD-L1 with intermediate affinity in solid tumor TME. As the secondary signaling motif, CD28 was chosen and tested along with CD3 zeta chain. The effector CAR T, named VPC1, cells specifically recognized PD-L1 expressing HCC cells and exhibited rapid and robust cytotoxic activity in 2D and 3D culture experiments. In an HCC xenograft NSG mouse model, VPC1 CAR T cells significantly suppressed the tumor growth. More importantly, VPC-1-treated animals have well tolerated the CAR T therapy with no significant adverse manifestations during one month observation period and exhibited gradual weight gains since 3 days after CAR T cell injection.
[Conclusion] We hereby report that a new autologous PD-L1 CAR-T therapeutic is capable of eradicating solid tumors expressing PD-L1, which would significantly potentiate efficacies of current conventional and immunotherapeutic strategies.
Citation Format: Kyung-Sik Lee, Hye-Seong Park, Guk-Yeol Park, Gi-Chan Lee, Eun-Ji Choi, Jae-in Yu, Seung-Joo Yang, Mihwa Kim, Yoonjoo Choi, Je-Jung Lee, Joon Haeng Rhee, Bum Chan Park, Jae Eun Park. Development of an anti hepatocellular carcinoma CAR T strategy targeting PDL1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6189.
Abstract 621: ZL-1211 exhibits robust anti-tumor activity by enhancing ADCC and activating innate and adaptive immunity in CLDN18.2-high and -low expressing gastric cancer models
Authors: Konno Hiroyasu , Lin Tracey , Sun Bee-Chun , Wu Renyi , Szeto Christopher , Bellovin David , Hsu Karl , Kabbarah Omar 
Published: June 2022

Abstract
CLDN18.2 (Claudin18.2)-targeting therapeutic antibodies have shown promising clinical efficacy in ~30% of gastric cancers expressing high levels of CLDN18.2 and less pronounced activity in the majority of low expressing malignancies. ZL-1211 is a monoclonal antibody targeting CLDN18.2 engineered to promote enhanced ADCC with the goal of achieving more potent activity in a wider spectrum of high- and low-CLDN18.2 expressing tumors than the leading clinical benchmark. To further assess the potency of ZL-1211, we utilized a panel of gastric tumor cell lines that endogenously express CLDN18.2 and more accurately reflect target levels in human gastric tumors than engineered overexpressing models. ZL-1211 demonstrated more robust in vitro ADCC activity than clinical benchmark not only in CLDN18.2-high but also -low expressing gastric cell lines. Greater anti-tumor efficacy was also observed in mouse xenograft models with CLDN18.2-high, -medium, and low-expressing gastric cell lines in response to treatment with ZL-1211 compared to the clinical benchmark. NK cell depletion abrogated ZL-1211-mediated ADCC activity in vitro. ZL-1211 efficacy in vivo was also dependent on the presence of an NK compartment, as CLDN18.2-expressing gastric tumors grown in Balb/c nude with an intact NK function were sensitive to ZL-1211 treatment, while NOD-SCID with partially competent NK activity exhibited minimal response, and NCG without NK cells did not display any evidence of in vivo efficacy. Strikingly, NK cells strongly induced an inflammatory response in response to ZL-1211 treatment, including increased IFNγ, TNFα, and IL-6 production. Interestingly, ZL-1211 treatment led to NK cell and monocyte stimulation and enhanced CD8+ T cell activation, suggesting a mechanism of action that not only involves innate but also adaptive immunity. Taken together, our data suggest that ZL-1211 more effectively targets CLDN18.2-high gastric cancers as well as -low expressing malignancies that are not eligible for treatment with the leading clinical benchmark by inducing a robust ADCC response and activating innate and adaptive immunity to enhance anti-tumor efficacy. Clinical activity of ZL-1211 is currently under evaluation in a Phase I clinical trial (NCT05065710).
Citation Format: Hiroyasu Konno, Tracey Lin, Bee-Chun Sun, Renyi Wu, Christopher Szeto, David Bellovin, Karl Hsu, Omar Kabbarah. ZL-1211 exhibits robust anti-tumor activity by enhancing ADCC and activating innate and adaptive immunity in CLDN18.2-high and -low expressing gastric cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 621.