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{"title":"Abstract B199: Potent induction of immunogenic cell death by PT-112","authors":"T. Yamazaki, T. Ames, L. Galluzzi","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B199","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B199","url":null,"abstract":"Purpose: To characterize the ability of PT-112 to induce immunogenic cell death (ICD) in vitro and in vivo. Background: PT-112 is a novel chemical entity consisting of a platinum core conjugated to a pyrophosphate and diaminocyclohexane groups. In vitro studies demonstrated that PT-112 has both cytostatic and cytotoxic effects on human cancer cells, two effects that are seen in the absence of robust binding to nuclear DNA. Accordingly, PT-112 potency is largely unaffected by functional DNA repair pathways, suggesting that PT-112 operates with mechanisms that differ from conventional DNA-damaging chemotherapies. PT-112 is currently under phase I/II clinical development in patients with solid tumors and hematologic malignancies, both as monotherapy and in combination with a PD-L1 inhibitor. Interim reports have established encouraging tolerability and signals of single-agent anticancer activity. Previous work with human colorectal cancer HCT-116 cells demonstrated that PT-112 causes the release of ICD-relevant damage-associated molecular patterns (DAMPs). ICD is a particularly relevant form of cell death for cancer therapy as it can drive tumor-targeting immune responses of clinical relevance. Here, we tested the ability of PT-112 to induce bona fide ICD in murine breast carcinoma TSA cells by in vitro DAMP release studies and in vivo gold-standard vaccination experiments. Methods: TSA cells were exposed to PT-112, cisplatin (negative ICD control) or mitoxantrone (MTX, positive ICD control) at different concentrations for 24 and 48 hours, followed by cytofluorometric assessment of cell number, viability, cell cycle distribution and exposure of the membrane-assocaited DAMP calreticulin (CRT). In addition, culture supernatants were assayed for the release of two other DAMPs, namely ATP and HMGB1, by luminometric tests and ELISA, respectively. BALB/c mice were vaccinated with TSA cells succumbing to optimal PT-112 (or MTX and cisplatin, as positive and negative controls, respectively) concentrations or mock vaccinated (with PBS). After 14 days this was followed by a rechallenge with living TSA cells and scoring of tumor-free survival (TFS) and tumor growth. Results: In vitro, PT-112 caused a robust cytostatic and cytotoxic effect on TSA cells that was accompanied by robust CRT exposure, ATP secretion and HMGB1 release. In line with such an ICD-compatible profile, 10/10 mice vaccinated with PT-112-treated TSA cells were tumor-free after the 1st rechallenge, and also rejected a subsequent challenge performed 1 month later, suggesting the establishment of long-term immunologic anticancer memory. As expected, cisplatin-treated TSA cells failed to mediate a similar effect (TFS at D7 after rechallenge: 10%), as did the mock vaccination arm (TFS at D7: 20%). MTX-treated cells conferred partial protection (TFS at D7: 40%), and the developing tumors had significantly delayed kinetics as compared to tumors evolving in mock-vaccinated mice. Conclusions: In the T","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"18 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121880670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B187: Origins of neoantigens for the major histocompatibility complex class I pathway","authors":"E. Sroka, R. P. Martins, Chrysoula Daskalogianni, Sébastien Apcher, R. Fåhraeus","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B187","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B187","url":null,"abstract":"Neoantigens are antigens generated by somatic mutations that can be recognized by the host immune system, firstl described as differentiating or tumor antigens back in 80s and 90s in research related to mice melanoma and breast cancers carried out by Houghton’s and Cheever’s teams, respectively. Now, during the era of potent immunotherapies, cancer vaccines and checkpoint inhibitors (CTLA-4, PD-1), neoantigens again attract much of scientists’ attention. With the use of cutting-edge technologies like next-generation sequencing, mass spectrometry, and predictive algorithms, more is known about antigen presentation and the links between occurrence of somatic mutations in cancer cells and antigen recognition by CD8+T-cells. Interestingly, discoveries of alternative sources of antigenic peptides (e.g., DRIPs and PTPs) challenged the notion about full-length proteins being the main supplier of material for MHC class I pathway and shifted focus of search for new sources to ribosomal scanning during pioneer round of translation. Despite the fact that pathways involved in processing and presentation of peptides have been thoroughly studied, there is still more to be learned about the sources of peptide material for the endogenous and exogenous MHC class I pathways. Based on works related to Epstein-Bar virus, it has been shown that MHC class I immune surveillance is directly correlated with the mechanism that regulates protein synthesis. Together with other results, it highlights the importance of pre-mRNA and mRNA processing in providing antigenic peptides for MHC class I surveillance. Here we revise some significant research related to the production of alternative antigenic peptides, their importance in cancer research, immunosurveillance and generation of tolerance. The lack of animal models to study the origin of alternative antigenic peptides hinders research in the field of neoantigens. I will describe results of the presentation of intron-derived antigenic peptides in mice model developed by our team. Citation Format: Ewa Maria Sroka, Rodrigo Prado Martins, Chrysoula Daskalogianni, Sebastien Apcher, Robin Fahraeus. Origins of neoantigens for the major histocompatibility complex class I pathway [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B187.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"120 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124790290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B195: Chemical probes for exploring muropeptide-pattern recognition receptor interactions in cells","authors":"Yen-Chih Wang","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B195","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B195","url":null,"abstract":"Peptidoglycan fragments from the bacterial cell wall activate innate immune signaling pathways and limits infections in animals. Indeed, recent studies from the Hang and Mucida laboratories have shown that E. faecium secreted peptidoglycan hydrolase (SagA) generates smaller peptidoglycan fragments, muropeptides, which can enhance host epithelial barrier integrity and enteric pathogen tolerance. However, the direct biochemical interactions of muropeptides with their proposed pattern recognition receptors have been challenging to characterize. Here, I report the chemical synthesis of photoaffinity probes for the analysis of muropeptide-pattern recognition receptor interactions in cells. These studies reveal direct biochemical interactions of muropeptide with pattern recognition receptors and other potential cofactors in mammalian cells. Further characterization of muropeptide-pattern recognition receptor and cofactor complexes will be important for elucidating fundamental mechanisms of innate immunity and inflammation-associated diseases and cancer. Citation Format: Yen-Chih Wang. Chemical probes for exploring muropeptide-pattern recognition receptor interactions in cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B195.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115080872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B193: PD-L1 somatic alterations predict sensitivity of advanced prostate cancer patients to platinum-based chemotherapy","authors":"P. Vlachostergios, Aileen Lee, Charlene Thomas, P. Patel, A. Hackett, N. Rashid, A. Molina, D. Nanus, H. Beltran, S. Tagawa","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B193","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B193","url":null,"abstract":"Background: The immune contexture of cancers and the tumor-immune system interplay are becoming increasingly understood. Immunotherapy with checkpoint inhibitors is an established treatment for several cancer types, with PD-L1 immunohistochemical expression as a companion predictive biomarker in some tumors. Checkpoint blockade is not an established treatment for patients with advanced PC (castration-resistant or neuroendocrine); however, platinum compounds have shown activity. The aim of this study was to assess the impact of PD-L1 somatic alterations on clinical response to platinum-based chemotherapy in men with advanced PC. Methods: Records of advanced PC patients from our Precision Medicine cohort who were treated with platinum-containing chemotherapy with available tissue samples and information on known prognostic factors were reviewed. By whole-exome sequencing (WES) we assessed for presence of mutations and copy number alterations in CD274 gene (encoding PD-L1). Kaplan Meier curves, univariable and multivariable Cox regression analyses were used to predict time to PSA progression-free survival (PSA-PFS), radiographic progression-free (rPFS) and overall survival (OS) after platinum chemotherapy initiation. Results: Thirty-one men, median age 69 years (range 50-85), were studied. Eight patients (26%) were NEPC based on histologic features. Nineteen had visceral metastases (16 liver, 11 lung, 1 brain) and 25 had bone metastases. 26 patients received carboplatin, 8 received cisplatin (4 received both sequentially, with initial platinum used for this analysis). Most received platinum in combination with other drugs, most commonly paclitaxel (N=11) and etoposide (N=12). CD274 somatic alterations (mutations or/and copy number changes) were associated with a significantly longer rPFS (median rPFS: 8 months) compared to patients with wild-type PD-L1 (median rPFS: 4 months, P=0.022). PD-L1 alterations were less frequent in patients with bone metastases (2/22 vs 4/9, P=0.043). There was no significant difference in PSA-PFS or OS among patients with PD-L1 wild-type and mutated tumors. On multivariate analysis (adjusted for Gleason score, PSA, alkaline phosphatase, lactate dehydrogenase, hemoglobin, visceral metastases, performance status, use of opioids), PSA (P=0.049) and presence of visceral metastases (P=0.048) were independent prognostic indicators for OS. Conclusions: PD-L1 somatic alterations may confer sensitivity to platinum-based chemotherapy in men with advanced PC who receive platinum-based chemotherapy. Prospective validation studies in such patients are needed to confirm these findings. Citation Format: Panagiotis J. Vlachostergios, Aileen Lee, Charlene Thomas, Priyanka Patel, Amy L. Hackett, Naureen Rashid, Ana M. Molina, David M. Nanus, Himisha Beltran, Scott T. Tagawa. PD-L1 somatic alterations predict sensitivity of advanced prostate cancer patients to platinum-based chemotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EA","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"51 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133514495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B149: Real-time analysis of cell membrane protein and virus internalization using site-specific conjugation of protease-sensitive probes","authors":"Ross W. Cheloha, Zeyang Li, Djenet Bousbaine, Andrew W. Woodham, P. Perrin, J. Volarić, H. Ploegh","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B149","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B149","url":null,"abstract":"Reagents that label specific subsets of cells are broadly useful for the treatment of cancer and modulation of cells of the immune system. Labeling is often achieved through the identification and characterization of proteins specifically expressed on selected cells but not others. Knowledge of cell membrane protein routing dynamics can be leveraged to efficiently deliver cytotoxic or immune stimulating payloads. The most common method for monitoring internalization relies on labeling proteins with antibodies modified with a fluorophore or other tag that can also be used to report on whether the protein of interest has been internalized. This approach requires indirect methods, such as multiple rounds of cell staining, to differentiate extracellular protein from protein that has been internalized and recycled to the cell surface. Here we report a method for the characterization of protein internalization in real time through the sortase-mediated, site-specific labeling of single domain antibodies or viral proteins with a newly developed, cathepsin-sensitive quenched-fluorophore probe. This approach allows quantitative measurement of the movement of proteins into protease-containing endosomes in real time in live cells. This method revealed variation in the rate of internalization for different cell surface receptors and allowed for kinetic characterization of influenza virus internalization. These findings help to explain the utility of certain single domain antibody-antigen conjugates for inducing humoral immune responses. The tools and methods described here should be useful for the identification of proteins expressed on target cells that are ideal for antibody-mediated drug delivery or for promotion of specific types of immune responses. Citation Format: Ross W. Cheloha, Zeyang Li, Djenet Bousbaine, Andrew Woodham, Priscillia Perrin, Jana Volaric, Hidde L. Ploegh. Real-time analysis of cell membrane protein and virus internalization using site-specific conjugation of protease-sensitive probes [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B149.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"23 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126443855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B200: Single-cell RNA-sequencing (ScRNA-seq) reveals broad heterogeneity among CD8 T-cells during chronic viral infection and identifies a critical role for CD4 help in promoting the differentiation of a potent cytotoxic CD8 T-cell subset","authors":"Ryan Zander, David M. Schauder, G. Xin, C. Nguyen, Xiaopeng Wu, W. Cui","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B200","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B200","url":null,"abstract":"During chronic viral infection and cancer, CD8 T-cells undergo a differentiation process commonly referred to as T-cell exhaustion. This process is traditionally defined by a stepwise loss of effector functions, eventually leading to cell death. Despite their inability to completely clear the infection, exhausted T-cells are still necessary for limiting viral replication during infection. Thus, it has been proposed that functional adaptation is a more appropriate term for T-cell exhaustion, as CD8 T-cells may be undergoing a multifaceted process of differentiation to better meet the needs of a chronic infection. In line with this hypothesis, it has recently been demonstrated that CD8 T-cells responding to chronic infection are non-homogenous and can be compartmentalized into at least two major subsets, with a TCF-1+ subset serving as a progenitor population that can give rise to a more terminally exhausted TCF-1- subset. However, whether additional heterogeneity exists among CD8 T-cells responding to persistent infection remains unclear. Here, we used ScRNA-seq to fully characterize the heterogeneity of CD8 T-cells during chronic LCMV Cl13 infection. We identified that several transcriptionally distinct subsets of CD8 T-cells develop during chronic LCMV infection, with 3 particular clusters, Slamf6, Pdcd1, and Cx3cr1 cell subsets dominating the antiviral CD8 T-cell response. Importantly both ScRNA-seq and flow cytometric analyses demonstrated that differential expression of cell surface receptors CX3CR1 and Ly108 (encoded by Slamf6) can distinguish these 3 major T-cell subsets. Notably, Ly108 cells shared similar characteristics to the previously described progenitor population and displayed elevated expression of TCF-1. Conversely, CX3CR1 CD8 T-cells displayed increased expression of killer cell lectin-like receptors Klre1 and Klra9, and the TFs T-bet and Zeb2, whereas CX3CR1-Ly108- (DN) cells exhibited elevated expression of multiple co-inhibitory receptors and the TFs Eomes and Nr4a2. Ex vivo functional analyses further indicated that Ly108 CD8 T-cells exhibit an enhanced capacity to co-produce IFN-γ and TNF-α upon GP33 peptide stimulation, whereas CX3CR1 CD8 T-cells display augmented cytotoxicity against peptide-pulsed targeT-cells. Sc trajectory modeling using Monocle analyses predicted that Ly108 CD8 T-cells give rise to both CX3CR1 and DN subsets, with the DN subset branch appearing closer in pseudotime to the Ly108 progenitor subset. To determine the in vivo differentiation trajectory, proliferative potential, and phenotypic stability of these 3 subsets, we performed adoptive transfer experiments using congenically marked CD8 T-cells. Importantly, and consistent with our Monocle predictions, our results demonstrate that Ly108 CD8 T-cells display robust secondary proliferation and give rise to both CX3CR1 and DN subsets. By contrast, CX3CR1 cells retained high CX3CR1 and T-bet expression and did not differentiate into Ly108 or DN CD8 T-cel","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"51 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127847501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B150: STING acquired species-specific motifs to control alternative immune responses","authors":"C. O. Mann, D. King, P. Kranzusch","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B150","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B150","url":null,"abstract":"Stimulator of Interferon Genes (STING) is an adaptor protein critical for downstream signaling during recognition of mislocalized cytosolic DNA. STING activation requires recognition of a unique second messenger 2′–5′, 3′–5′ cyclic GMP–AMP (2′3′ cGAMP) synthesized by the pathogen recognition receptor cyclic GMP–AMP synthase (cGAS). Due to its broad expression in most tissues, and ability to respond to different endogenous and foreign small molecules, STING is emerging as a promising drug target for cancer immunotherapy and treatment of autoimmune diseases. However, it remains unknown how the single adaptor protein STING controls distinct transcriptional outputs leading to production of type I interferon, proinflammatory cytokine responses or autophagy. Here we present surprising evidence for the ancient origins of the cGAS-STING signaling pathway by discovery of bacterial cGAS-like enzymes and complete functional cGAS-STING pathways in lower metazoans. Our previous structural data demonstrate that human and metazoan STING proteins share a common architecture that couples ligand binding with conformational changes and allows signal activation. However, it remained unclear how alternative STING conformations control different downstream signaling outputs, and which motifs are responsible for recruitment of the downstream factors controlling each pathway. We have now combined a phylogenetic and biochemical approach to explain the conserved elements that regulate STING downstream signaling events. Our analysis identifies new immune pathway-specific regulatory motifs acquired by distinct STING species, and we are currently focused on identifying the recruited factors important for controlling human STING signaling. Together, our results explain the molecular basis for distinct STING downstream signaling, and provide new insights for the rational design of STING pathway-specific therapeutics. Citation Format: Carina C. de Oliveira Mann, David S. King, Philip J. Kranzusch. STING acquired species-specific motifs to control alternative immune responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B150.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124560984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B158: Clinical features and management of mantle cell lymphoma","authors":"F. Grifi, S. Bougherira, A. Djenouni","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B158","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B158","url":null,"abstract":"Introduction: Mantle cell lymphoma (MCL) is a relatively uncommon subtype of lymphoid malignancy and represents 3%–10% of malignant lymphoma, and now appears as a biologic and therapeutic model in the understanding and treatment of hematologic malignancies. Diagnostic procedures include histomorphology, immunophenotype (CD5+, CD19/20+), Ki-67 staining and mandatory detection of cyclin D1 overexpression or t(11;14)(q13;q32). The treatment is very heterogenous and the evolution is marked by numerous relapses. Patients and Methods: During the period from January 2012 to January 2017, we conducted a retrospective and prospective study on the epidemiologic, clinical, prognostic and therapeutic profile of mantle lymphoma. This mono-centric study focused on 20 cases managed in the hematology department of the Annaba University Hospital. The diagnostic method was based on lymph node biopsy and immunophenotyping. The clinical characteristics (according to the international prognostic index of MCL [MIPI]), anatomopathologic (Ki67, blastoid appearance) and radiologic were collected, as well as the different treatment lines were reported. It should be noted that no patient has benefited from a cytogenetic study in search of t (11; 14). Results: Mean age was 63.5 years (range 44- 87). There was a predominance of male subjects with a sex ratio of 1.86. Nodal localization was found in 85%, followed by involvement of the spleen in 20%. The extranodal location is dominated by gastrointestinal involvement (multiple lymphomatous polyposis 25%) and ENT (10%). Almost all patients had ECOG 0-1. Patients had extensive stages (III and IV) of ANN ARBOR. Bone marrow infiltration was found in 35% of cases. The prognostic classification according to MIPI allowed us to classify our cohort into 3 groups as follows: high (n = 12), intermediate (n = 5) and low (n = 3) score. The high proliferation index (+ 50%) in 3 of our patients with the blastoid form in 2 cases were noted. Therapeutically, 19 patients received immuno-chemotherapy according to different protocols: alternating R-CHOP / R-DHAP (7 pts), R-CHOP (4 pts), VR-CAP (4 pts), R-bendamustine (2 pts) and R-mini CHOP (2 pts) with an average number of courses of all protocols 3 (1-6). Maintenance treatment with rituximab every 2 months for 2 years was indicated in 3 patients (2 of whom are still on treatment). The overall response rate is 79%; failure was found in 2 patients. After a median follow-up time of 21 months (5 days-63 months) of the 15 patients in response, 10 are alive in persistent response; late relapse occurred in 2 patients. We deplore 5 deaths including 2 toxic, versus progression of the disease for others. Conclusion: Mantle cell lymphoma is a heterogeneous pathology known to be aggressive and incurable. In spite of recent therapeutic advances, including the provision of immunotherapy (rituximab), the addition of aracytin to high-dose induction and therapeutic intensification followed by autologous-hemato","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"11 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115583624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B173: G protein coupling signaling as regulators of dendritic cell maintenance and function in immune responses","authors":"Dan Liu, J. Cyster","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B173","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B173","url":null,"abstract":"Dendritic cells (DCs) are well known as the professional antigen presenT-cells (APCs), which can scan peripheral tissues where they can recognize, uptake, process and present all kinds of antigens, including pathogens and tumor antigens, to antigen specific naive T-cells within the lymphoid organs. In these processes, DCs form a remarkable bridge between innate and adaptive immunity by interacting with various lymphoid and myeloid cells. DCs originate from the bone marrow hematopoietic progenitor cells and DC precursors migrate from blood to tissues for developing into immature DCs. Upon activation, DCs migrate to stimulate T-cells and induce immune responses to protect our bodies. However, the mechanism for maintenance and activation of DCs on the local microenvironment is largely unknown. As GPCR signaling has important roles in many cellular process, including cell division, survival, migration and adhesion. Using competitive mixed BM chimaera, I checked some molecules involved in GPCR signal pathways, and found that geneA was required intrinsically in the maintenance of CD4+ conventional DCs (cDCs) in the spleen, as evidenced by observation that geneA-deficient CD4+ DCs were dramatically decreased in spleen but increased in blood. By in vivo 3min CD45-PE labeling assay, cells exposed to the vascular compartment in spleen can be selectively labeled. With this method, I found without geneA, CD4+ DCs had disadvantage to be maintained in the blood-exposed region within the spleens under the shear flow stress. I further showed that geneA-deficient CD4+ DCs had disadvantage to uptake blood-derived Sheep-blood cells (SRBCs). Besides this stimulation, this signal also controlled CD4+ DCs activation in response to different kinds of TLR stimulators. By OT-II adoptive transfer system, geneA-expressing DCs were required to support T-cell proliferation and differentiation efficiently. Therefore, these results demonstrate a key role of G protein-coupled receptor signaling in promoting the maintenance and activation of DCs, and reveal a mechanism in DC positioning in vivo. Thus, it will broaden our understanding of GPCR signaling in DC immunology, which is pivotal for modulating DCs for vaccines and therapies against pathogens, autoimmune diseases and tumors. Citation Format: Dan Liu, Jason G. Cyster. G protein coupling signaling as regulators of dendritic cell maintenance and function in immune responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B173.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"96 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128382291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B172: Molecular mechanisms of dual-specificity phosphatase 22 (DUSP22) in suppression of tumorigenesis: The potential involvement of the EGFR/PD-L1 axis","authors":"Wen-Jye Lin, Cheng-Wei Chang, Hsiu‐Ping Lin, Hui‐Min Ho","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B172","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B172","url":null,"abstract":"DUSP22, belonging to members of the dual-specificity phosphatases (DUSPs) family, can control the activity of various protein kinases and transcription factors through the dephosphorylation process. Many DUSP22-targeted proteins are involved in signaling pathways that are crucial for tumorigenesis, and inflammation. Genetic alteration of DUSP22 or DUSP22 downregulation was observed in some cancers. However, little is known about the roles of DUSP22 during tumor suppression. Here, utilizing TGCA databases, our analysis showed low DUSP22 expression is associated with shorter disease-free survival of lung and prostate cancer patients. The IL-6/STAT3 and EGFR/ERK1/2 axes are generally recognized as an important oncogenic and mitogenic pathway in prostate cancer. We found that DUSP22 expression markedly reduced p-STAT3 (Tyr705), and p-EGFR (Tyr1068)/p-ERK1/2 expression levels after IL-6 and EGF stimulation, respectively, in prostate cancer cells. Similarly, DUSP22 can inhibit the EGFR/ERK1/2 axis in lung cancer cells that harbor EGFR exon 19 deletion mutation, supporting a repressive role for DUSP22 in regulating growth receptor signaling pathways. In addition, we found the exogenous expression of DUSP22 significantly reduced the cell growth of prostate and lung cancer cells. More importantly, DUSP22 can serve as a negative regulator of androgen receptor in prostate cancer cells through reducing EGF-induced AR phosphorylation and inhibiting DHT-mediated nuclear AR translocation. Taken together, our current data indicate that loss of DUSP22 function or DUSP22 downregulation may accelerate lung and prostate tumorigenesis through EGFR-dependent pathways. Importantly, it has been reported that increased PD-L1 expression by EGFR activation mediates the immune escape in EGFR-driven lung cancer (NSCLC). We found that the inhibition of the EGFR signaling by DUSP22 can reduce PD-L1 expression in both lung and prostate cancer cells, suggesting that loss of DUSP22 function in cancer cells may not only enhance cell growth, but also potentially repress antitumor immunity through upregulation of PD-L1. Our findings implicate that anti-PD1/PD-L1 therapy could be a potential option if lung or prostate cancer patients are found with low DUSP22 expression. Currently, we are using multiple approaches to elucidate molecular mechanisms of DUSP22 ablation for accelerating lung and prostate tumorigenesis in vivo. Citation Format: Wen-Jye Lin, Cheng-Wei Chang, Hsiu-Ping Lin, Hui-Min Ho. Molecular mechanisms of dual-specificity phosphatase 22 (DUSP22) in suppression of tumorigenesis: The potential involvement of the EGFR/PD-L1 axis [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B172.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124001093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}