bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1590: An experimental tumor model resistant to anti-PD-1 is sensitive to local mRNA immunotherapy
Authors: Bernardo Marie , Tolstykh Tatiana , Zhang Yu-an , Bangari Dinesh S. , Cao Hui , Heyl Kerstin A. , Lee Joon Sang , Malkova Natalia , Pollard Jack , Qu Hui , Sun Fangxian , Wiederschain Dmitri , Wagenaar Timothy R. 
Published: July 2021

Abstract
Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. In an effort to better understand acquired resistance to checkpoint blockade, we generated a mouse tumor model exhibiting in vivo resistance to anti-PD-1 antibody treatment. MC38 tumors acquired resistance to PD-1 blockade following serial in vivo passaging. Lack of sensitivity to PD-1 blockade was not attributed to dysregulation of PD-L1 or β2M expression, as both were expressed at similar levels in parental and resistant cells. Similarly, IFNγ signaling and antigen processing and presentation pathways were functional in both parental and resistant cell lines. RNA-sequencing revealed substantial differences in global gene expression, with tumors resistant to anti-PD-1 displaying a marked reduction in expression of immune-related genes relative to parental MC38 tumors. Indeed, resistant tumors exhibited reduced immune infiltration across multiple cell types, including T and NK cells. Pathway analysis revealed activation of TGFβ and Notch signaling in anti-PD-1 resistant tumors, and activation of these pathways was associated with poorer survival in human cancer patients. While pharmacological inhibition of TGFβ and Notch in combination with PD-1 blockade decelerated tumor growth, local administration of a mixture of mRNAs encoding immune-stimulatory cytokines (IL12sc, GM-CSF, IL15s and IFNα) potently induced regression of resistant tumors and resulted in complete tumor remission. Overall, this study describes a novel anti-PD-1 resistant mouse tumor model and underscores the role of two well-defined signaling pathways in response to immune checkpoint blockade. Furthermore, our data highlights the potential of intratumoral mRNA therapy in overcoming acquired resistance to PD-1 blockade.
Citation Format: Marie Bernardo, Tatiana Tolstykh, Yu-an Zhang, Dinesh S. Bangari, Hui Cao, Kerstin A. Heyl, Joon Sang Lee, Natalia Malkova, Jack Pollard, Hui Qu, Fangxian Sun, Dmitri Wiederschain, Timothy R. Wagenaar. An experimental tumor model resistant to anti-PD-1 is sensitive to local mRNA immunotherapy [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 1590.
Abstract 1600: Cancer driver screens identifyregulators of immune checkpoint blockade therapy response
Authors: Zhou Wenrong , Peng Zhengang , Huang Dawei , Long Min , Song Tianyu , Ni Siyuan , Cang Yong 
Published: July 2021

Abstract
Cancer mutations play essential roles in tumor development by promote cell proliferation or immune evasion. However, some recent researches indicate that cancer cells with these mutation burden also expose their vulnerability to immune-based therapies such as checkpoint blockade. Here we performed comprehensive CRISPR knockout library screens in syngeneic mouse models on cancer driver mutation genes. We identified a set of genes including Kmt2d, Arid2, Rhob, Eloc, Ptpn11 and Xpo1, which have high frequency mutation in several human cancer types and their deficiency made tumor cells better respond to anti-PD-1 treatment. Furthermore, some of these deletions were validated to sensitize the tumor cells to cytotoxic T cells by in vitro co-culture with CD8+ T cells. The findings of Kmt2d was in accordance with a recent report for its role as a sensitizing modulator of immune checkpoint blockade from mouse model and patient prediction. These findings provide a new insight for understanding the interaction between the tumor heterogeneity and microenvironment. These results revealed CRISPR in vivo screen as a robust tool for both context and target discovery for tumor immunotherapy.
Citation Format: Wenrong Zhou, Zhengang Peng, Dawei Huang, Min Long, Tianyu Song, Siyuan Ni, Yong Cang. Cancer driver screens identifyregulators of immune checkpoint blockade therapy 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 1600.
Abstract 1618: Inhibition of lung tumorigenesis by a novel small molecule CA170 targeting the immune checkpoint protein VISTA
Authors: Pan Jing , Chen Yao , Zhang Qi , Khatun Achia , Palen Katie , Wang Li , Yang Chuanjia , Johnson Bryon D. , Myers Charles R. , Sei Shizuko , Shoemaker Robert H. , Lubet Ronald A. , Wang Yian , Cui Weiguo , You Ming 
Published: July 2021

Abstract
Immunotherapy using monoclonal antibodies to block immune checkpoints is becoming a mainstream therapy for multiple late-stage cancers owing to their efficacy in improving clinical outcomes. However, relatively low response rates and persistent clinical side effects indicate the need for additional strategies to block immune-suppressive pathways. VISTA (V-domain Ig Suppressor of T cell Activation), which is expressed on cells of the myeloid and lymphoid lineages, is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. We found that CA170, a novel orally bioavailable tripeptide small molecule antagonist of VISTA and PD-L1/PD-L2, has potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHC-II-directed KRAS peptide vaccine. Flow cytometry and single cell RNA sequencing (scRNA-seq) revealed that CA170 increases CD8+ T cell infiltration and effector functions by decreasing the tumor infiltration of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs), while the KRAS vaccine primarily induces expansion of CD4+ effector T cells. Inhibition of VISTA by CA170 has strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and promotes an adaptive T cell tumor-specific immune response that enhances efficacy of the KRAS vaccine.
Citation Format: Jing Pan, Yao Chen, Qi Zhang, Achia Khatun, Katie Palen, Li Wang, Chuanjia Yang, Bryon D. Johnson, Charles R. Myers, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Weiguo Cui, Ming You. Inhibition of lung tumorigenesis by a novel small molecule CA170 targeting the immune checkpoint protein VISTA [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 1618.
Abstract 1619: A prognostic score for advanced non-small cell lung cancer with PD-1/L1 inhibitors
Authors: Yuan Qianyu , Du Mulong , Christiani David 
Published: July 2021

Abstract
Background: Programmed death 1 (PD-1)/programmed death-legend 1(PD-L1) inhibitors have shown clinical benefits for a proportion of advanced lung cancer patients. This study aimed to develop a prognostic store with routinely available variables to identify non-small cell lung cancer (NSCLC) patients who likely benefit from PD-1/L1 inhibitors.
Methods: 412 patients who received PD-1/L1 inhibitors were retrospectively collected from Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH) between Nov 2013 and Jan 2018. Demographic, clinical, and common laboratory tests were collected. Penalized Cox proportional hazard model with group minimax concave penalty (MCP) penalty was applied for variable section and coefficient estimation. Model performance was assessed by calculating area under the receiver operating curves (AUC). A prognostic score was developed to categorize advanced NSCLC patients into good, intermediate and poor groups.
Results: Median PFS was 3.6 (95% CI: 2.9 - 4.3) months, median OS was 18.4 (95% CI: 14.2-24.9) months. A prognostic scoring model incorporating the weighted coefficients of PD-L1 expression level, EGFR mutation status, ECOG performance status, and albumin level was developed. Median PFS were 1.7 (95% CI: 1.5-2.1) vs 3.2 (95% CI: 2.7-6.3) vs 6.2 (95% CI: 4.9-9.7) months for the poor, intermediate and good groups, respectively. Median OS were 8.2 (95% CI: 4.5-14.1) vs 14.9 (95% CI: 11.8-30.0) vs 34.7 (95% CI: 26.2 -NE) months for the poor, intermediate and good groups, respectively.
Conclusions: a prognostic score combining PD-L1 expression level, EGFR mutation status, ECOG performance status, and albumin level may help to identify advanced NSCLC patients who likely benefit from PD-1/L1 inhibitors.
Citation Format: Qianyu Yuan, Mulong Du, David Christiani. A prognostic score for advanced non-small cell lung cancer with PD-1/L1 inhibitors [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 1619.
Abstract 1622: Block-Removed Immunoglobulin Technology (BRITE) to enhance rituximab effector function by counteracting CA125/MUC16-mediated immunosuppression
Authors: Grasso Luigi , Kline J. Bradford , Nicolaides Nicholas C. 
Published: July 2021

Abstract
Rituximab is a CD20-targeting antibody that is the standard-of-care for patients with Non-Hodgkin Lymphoma (NHL) cases. Rituximab's mechanism of action includes complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) - herein referred to as Humoral Immuno-Oncology (HIO) mechanism. Recent clinical evidence suggest that high serum levels of the tumor-produced MUC16/CA125 protein has a negative impact on the effectiveness of rituximab clinical activity on up to 40% of follicular lymphoma patients. In this study we demonstrate that CA125 binds to rituximab and reduces its tumor cell killing activity. Moreover, we describe the generation of a rituximab variant, named NAV-006, using a proprietary technology called Block-Removed Immunoglobulin Technology (BRITE) that employs randomized amino substitution and high-throughput screening to identify HIO-refractory rituximab variants. Here, we demonstrate that NAV-006 is more refractory to the immunosuppressive effects mediated by CA125 as shown by its reduced CA125 interaction and increased HIO activity. These data warrants further investigation of NAV-006 as a next generation anti-CD20 antibody that could improve upon the efficacy of the parent rituximab in NHL patients with high levels of CA125.
Citation Format: Luigi Grasso, J. Bradford Kline, Nicholas C. Nicolaides. Block-Removed Immunoglobulin Technology (BRITE) to enhance rituximab effector function by counteracting CA125/MUC16-mediated immunosuppression [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 1622.
Abstract 1634: Siglec-15 knockout inhibits tumor growth in mouse model
Authors: Li Peixue , Yan Guofang , Wang Fuyang , Tang Xuzhen , Lin Qing 
Published: July 2021

Abstract
Several immune checkpoint blockers have been approved for treatment of certain cancers, which benefits a lot of patients with malignancies. However, the overall response rate to the current checkpoint blockers did not exceed 30% in many cases, stressing the importance of developing new immunotherapies. Siglec-15 is reported to be a critical immune suppressor functioning in parellel with PD1/PD-L1 pathway by Lieping Chen's lab in 2019. In order to verify the effect Siglec-15 in immune response against tumor growth, we generated Siglec-15 KO mice with CRISPR/Cas9 mediated genome editing and tested tumor establishment on this mice with syngeneic cell lines with or without human SIGLEC-15 overexpression. Our results showed that Siglec-15 KO inhibits tumor growth and enhances immune response in the tumor infiltrating leukocytes, supporting the role of Siglec-15 as a promising target for development of new immune checkpoint blocker.
Citation Format: Peixue Li, Guofang Yan, Fuyang Wang, Xuzhen Tang, Qing Lin. Siglec-15 knockout inhibits tumor growth in mouse model [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 1634.
Abstract 1644: Targeting type I IFN-regulated secretory profiles to overcome acquired anti-PD-L1 resistance
Authors: Shi Yuhao , Dolan Melissa , Mastri Michalis , Hill James W. , Eng Kevin , Ebos John M. 
Published: July 2021

Abstract
Therapeutic inhibition of PD-L1 has led to durable benefits for many cancer patients; however, acquired resistance is common. Dysregulated type I and II interferon (IFN) signalling on tumor cells can contribute to resistance via altered expression of IFN stimulated genes (ISGs) leading to immune-suppression and tumor promotion. In this study, we examined the role of type I IFN signaling following acquired resistance to PD-L1 blockade using an EMT6 mouse breast orthotopic tumor model that was initially responsive to treatment, but that later relapsed. Following selection of PD-L1 drug resistant (PDR) tumor cells, transcriptomic and proteomic analysis was used to identify a unique signature of secreted proteins associated with IFN signaling that was then validated using published preclinical and clinical datasets. Using genetic and therapeutic approaches to block PD-L1 in vitro, we found PDR secretory signatures to be enhanced after type I IFN stimulation. In vivo, inhibition of specific ISGs (IL-6) or ISG regulators (IFNAR1) led to enhanced anti-tumor effects in PDR models, compared to parental controls. Together, these results identify a secretory profile associated with acquired resistance to PD-L1 blockade that may be modulated, in part, by a tumor-intrinsic PD-L1/IFN signaling crosstalk and suggest that selective targeting of secreted ISGs may provide benefit for patients after anti-PD-L1 treatment failure.
Citation Format: Yuhao Shi, Melissa Dolan, Michalis Mastri, James W. Hill, Kevin Eng, John M. Ebos. Targeting type I IFN-regulated secretory profiles to overcome acquired anti-PD-L1 resistance [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 1644.
Abstract 1654: Myeloid-dominated spontaneous tumor models as the tool for the evaluation of immune modulators
Authors: Zhai Xianzhi , Yang Yuying , Zhao Haoxia , Jiang Jingjing , Tang Xuzhen , Ji Qunsheng 
Published: July 2021

Abstract
BACKGROUND:Myeloid cells, such as TAMs and MDSCs and their correlation with solid tumor progression have been widely recognized. As researchers are turning their interests to explore myeloid related tumor models, spontaneous tumor models, which represent a natural development/progression of tumor under certain immune microenvironment, would be a valuable tool for such studies. Some traditional targeted drugs have been re-evaluated for their immune effects, for example, CDK inhibitors can trigger anti-tumor immunity beyond its cell cycle regulation. Methods:In prior studies we have identified two myeloid-dominant spontaneous tumor models, APCmin and MMTV-PyMT, which represented a myeloid-enriched(especially for gMDSCs) and low T cell infiltrated microenvironment compared to the congenic mice. Immune modulators including checkpoint inhibitors (aCTLA-4),NSAID (Celecoxib) and CDK4/6 inhibitor(Palbociclib) were applied to evaluate their efficacy to the two models and their influences on the immune microenvironment. RESULTS:As a result, CDK inhibitor Palbociclib showed a better curative effect on MMTV-PyMT model compared to aCTLA-4. It seems when aCTLA-4 only up-regulated T cell level, CDK inhibitor can both increase the tumor infiltrating T cells as well as decrease Treg and myeloid, which explain its good response on this myeloid-dominated model. In APCmin model, Celecoxib reduce adenomas and alleviate the anemia symptoms with its significant immune benefit: the increase of lymphocyte infiltration and the reversal of myeloid cell elevation. SUMMARY:In summary, APCmin and MMTV-PyMT can be used as good tool models for the evaluation of myeloid-related immune modulators.
Citation Format: Xianzhi Zhai, Yuying Yang, Haoxia Zhao, Jingjing Jiang, Xuzhen Tang, Qunsheng Ji. Myeloid-dominated spontaneous tumor models as the tool for the evaluation of immune modulators [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 1654.
Abstract 166: Real world genomic data supports combined use of SHP-2 and PD-1/PD-L1 inhibitors in solid tumors
Authors: Toral Keller 
Published: July 2021

Abstract
The identification of novel therapies, new strategies for combination of therapies, and repurposing of drugs approved for other indications are all important for continued progress in the fight against lung cancers. Antibodies that target immune checkpoints can unmask an immunologically hot tumor from the immune system of a patient. However, despite accounts of significant tumor regression resulting from these medications, most patients do not respond. In this study, we sought to use protein expression and RNA sequencing data from The Cancer Genome Atlas and two smaller studies deposited onto the Gene Expression Omnibus (GEO) to advance our hypothesis that inhibition of SHP-2, a tyrosine phosphatase, will improve the activity of immune checkpoint inhibitors (ICI) that target PD-1 or PD-L1 in lung cancers. We first collected protein expression data from the The Cancer Proteome Atlas (TCPA) to study the association of SHP-2 and PD-L1 expression in lung adenocarcinomas. RNA sequencing data was collected from the same subjects through the NCI Genetic Data Commons and evaluated for expression of the PTPN11 (SHP-2) and CD274 (PD-L1) genes. We then analyzed RNA sequencing data from a series of melanoma patients who were either treatment naïve or resistant to ICI therapy. PTPN11 and CD274 expression was compared between groups. Finally, we analyzed gene expression and drug response data collected from 21 non-small cell lung cancer (NSCLC) patients for PTPN11 and CD274 expression. From the three studies, we hypothesize that the activity of SHP-2, rather than the expression, likely controls the expression of PD-L1 as only a weak relationship between PTPN11 and CD274 expression in either lung adenocarcinomas or melanomas was observed. Lastly, the expression of CD274, not PTPN11, correlates with response to ICI in NSCLC.
Citation Format: Keller Toral. Real world genomic data supports combined use of SHP-2 and PD-1/PD-L1 inhibitors in solid tumors [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 166.
Abstract 1681: Correlation of BRCA1/2 mutations with response to immune checkpoint inhibitors in colorectal cancer
Authors: Jia Dong-Dong , Niu Yanling , Ma Tonghui , Shi Min 
Published: July 2021

Abstract
Background: BRCA1 and BRCA2 are involved in homologous recombination (HR) DNA repair. They have been found to promote both tumor initiation and progression. BRCA1/2 mutations lead to genomic instability and higher tumor mutation burden (TMB). Therefore, we hypothesized that BRCA1/2 mutations may be a predictor of immune checkpoint inhibitors (ICIs) efficacy. In the present work, we explored the correlation of BRCA1/2 mutations with TMB, high microsatellite instability (MSI-H), PD-L1 expression, tumor-infiltrating lymphocytes (TILs), and ICIs efficacy in colorectal cancer.
Methods: A total of 509 Chinese colorectal cancer patients were enrolled from January 2017 to January 2020 in our center. Targeted next-generation sequencing and PD-L1 immunohistochemistry (22C3 antibody) were performed in the tissues from patients. TCGA colorectal cancer cohort was used for characterizing TILs with CIBERSORT. The ICIs treatment cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of BRCA1/2 mutations with ICIs efficacy.
Results: In our cohort, the mutational frequency of BRCA1/2 genes was 9.04%. The median TMB was significantly higher in the BRCA1/2 mutations (Mut) group compared to the wild type (WT) group (52.4 vs 5.7 muts/Mb, P &lt; 0.0001). About 41.30% of patients have MSI-H in the Mut group, while 3.67% of patients display MSI-H in the WT group (P &lt; 0.0001). There was no association of BRCA1/2 mutations with PD-L1 expression (P = 0.172). In TCGA cohort, BRCA1/2 mutations can down-regulate regulatory T (T reg) cells (P = 0.0176) and up-regulate T follicular helper cells (P = 0.0042) and macrophages M1 (P &lt;0.0001). In MSKCC cohort, patients in the Mut group had significantly longer median overall survival after ICIs therapy (34 vs 13 months, HR: 0.37 [95%CI: 0.19-0.72], P = 0.0234).
Conclusions: Our data indicated that BRCA1/2 mutations are associated with increased TMB and MSI-H, but not with PD-L1 expression. And BRCA1/2 mutations can regulate TILs. Furthermore, BRCA1/2 mutations are associated with better response to ICIs, suggesting that they may be a useful predictor for ICIs efficacy in colorectal cancer.
Citation Format: Dong-Dong Jia, Yanling Niu, Tonghui Ma, Min Shi. Correlation of BRCA1/2 mutations with response to immune checkpoint inhibitors in colorectal 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 1681.
Abstract 1694: Validation of GVHD in humanized mouse model for preclinical efficacy screen
Authors: Liu Menglin , Cai Yingying , Xu Na , Zhang Ya , Xie Rou , Jia Lijun , Lin Qing 
Published: July 2021

Abstract
Bone marrow transplantation has been successfully and widely used to treat diseases such as leukemia and lymphoma. However, the complication Graft vs Host Disease (GVHD) is a serious hindrance in patients' outcome. Immunosuppressant such as Cyclosporine A has been used to decrease the GVHD occurrence, but the associated side-effect such as transplant rejection and opportunistic infection outweigh its benefit. Therefore, new medication to suppress GVHD without severe toxicity is urgently in need now. To build better preclinical platform for drug efficacy evaluation in GVHD, we have validated the GVHD model in both mouse host and humanized mouse host. We collected bone marrow cells and splenocyte from C57BL/6J (H-2d) mice and transplant to irradiated BALB/c (H-2b) mice to induce GVHD. In humanized model, we injected humanized NPI mice (NOD-Prkdcscid-Il2rgem1lDMO with CD34+ hematopoeitc stem cells (HSCs) reconstitution) with PBMCs from MHCII mismatched donors to trigger GVHD occurrence. In both models, we observed the typical clinical symptoms such as hollow back, inactiveness, body weight loss in transplanted mice. Humanized mice with transplantation start to die in 2 weeks. In the endpoint, we used FACS to analyze the cell population change in whole blood, spleen and lymph nodes, and found histological changes in GI tract and skin. Thus, this model is suitable to screen potential human-specific antibodies or new small molecules. We are also going to explore extra parameters to characterize the disease progression.
Citation Format: Menglin Liu, Yingying Cai, Na Xu, Ya Zhang, Rou Xie, Lijun Jia, Qing Lin. Validation of GVHD in humanized mouse model for preclinical efficacy screen [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 1694.