bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2334: Intratumoral classical complement pathway promotes tumor growth in renal cancer
Authors: Daugan Marie , Roumenina Lubka , Noé Rémi , Petitprez Florent , Sautès-Fridman Catherine , Fridman Wolf H. 
Published: August 2019

Abstract
Objective: The complement system has been considered for long as anti-tumoral effector in the context of monoclonal antibody therapy. Nevertheless, recent studies highlighted a pro-tumoral effect of complement, acting on angiogenesis, tumor cells proliferation and immunosuppression. The kidney is capable to produce a whole spectrum of complement components. Nevertheless, the role of complement activation for the progression of renal cancer remains poorly understood. In the present work we address the presence of complement components and their impact on the clinical outcome of patients with clear cell renal carcinoma (ccRCC). In addition, we evaluate the tumor growth of complement proteins-expressing tumor cell lines in complement-deficient mice.
Methods: The production of complement proteins by RCC lines was measured by RT-qPCR and by western blot (WB). Their expression in the tumor tissue was evaluated by immunohistochemistry and multicolor staining by immunofluorescence (IF) on sections from paraffin embedded tumors. The capacity of RCC cells-produced proteins to activate complement was evaluated by ELISA and western blot. The presence of complement was evaluated by immunohistochemistry on tumor sections from 3 retrospective cohorts composed by primary ccRCC patients (over 300 cases total). Complement producing tumor cell lines were grafted in WT and classical complement pathway deficient mice and the tumor growth was followed.
Results: We found that C1q is expressed in the ccRCC tumors by the infiltrating macrophages, having a particular phenotype. The remaining complement proteins are produced by the tumor cells. A dynamic interaction between the complement proteins produced by the tumor cells and the immune microenvironnement led to a local activation of complement revealed in vitro and in situ. The high level of C1q and complement activation correlated with a poor prognosis for patients. Moreover, the tumor growth was reduced in C1q-/- and C4-/- mice.
Conclusion: Early steps of the classical complement pathway can be activated locally and are associated with a pro-tumoral effect in mice models and in patients with renal cancer.
Keywords: renal cancer; C1q; classical pathway
Citation Format: Marie Daugan, Lubka Roumenina, Rémi Noé, Florent Petitprez, Catherine Sautès-Fridman, Wolf H. Fridman. Intratumoral classical complement pathway promotes tumor growth in renal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2334.
Abstract 2343: Immunogenetics of cancer and aging
Authors: Williams RMichael , Yunis Edmond J. 
Published: August 2019

Abstract
Antigen altered idiotype regulates specific immune responses (Cell Immunol. 1978: 4). Mendelian segregation of a given +/- phenotype defines an immune response gene (Benacerraf, Nobel). Autoimmunity producing anti-self clones must be eliminated or specifically suppressed, so a large portion of the antigenic repertoire resembles allogeneic MHC molecules (Medawar, Nobel). We proposed that exposure to many different allogeneic HLA molecules could cause specific immune suppression within the repertoire of epitopes and that these blank spots or holes in the universe of target antigens eventually would overlap with specificities including targets for eliminating pathogens such as viruses or tumor antigens. Some "holes" become large enough to result in an acquired immunodeficiency syndrome (AIDS) The opposite is also possible (Allogeneic Effect, Transplant Rev. 1972, 12; 141). This requires viable cells and cytokines released by host and/or donor. IR-genes for tumor resistance localize to the MHC. Class I/II MHC genes (Cancer Res. 1982; 35:1586) and NK cell receptor ligands (J. Stem Cell Res. 2007), regulate adaptive and innate immunity. We examined the combination of HLA specificities and the alleles of ligands of receptors of NK cells in breast cancer patients, HIV non progressors, and centenarians in Mexico. Immunological evaluation (CD4+,CD8+,CD19+ & NK cells and quantitative IgM, IgG, & IgA in breast cancer (BCA) patients in California. Overall survival (OS) depended on specificities (idiotypes) and the regulation of innate and adoptive immunity. The BCA patients and centenarians did not have HIV infection. People with more CD4 cells, more NK cells and more IgG, survive longer than those with the opposite immune profile. The immune specificity repertoire has evolved to avoid fatal autoimmunity, all orchestrated by T regs via T-cell antigen receptors and variable regions of Ig. The antigen receptors (CAR-T) and Ig variable region antigen receptors (Jerne, Nobel) are idiotypes, Single amino acid (AA) changes become altered "antigens" of the history of the patient: environment (e.g., microbiome), vaccination (e.g., BCG), and virus infections (Sendai or CMV in mice, HIV and/or others like HPV in man). This is true for single AA changes in both mice (H-2 mutants) and man; NK cell receptor ligands (Thr v Met). The results show profound effects on survival. Data, including MHC and NK receptor ligand phenotypes, OS and immunological evaluation of patients/people will be presented. Immunogenetic profiles of cancer survivors and long lived individuals are similar to those of HIV long term non progressors. Our data support our Immunogenetic Theory of Cancer and Aging.
Citation Format: RMichael Williams, Edmond J. Yunis. Immunogenetics of cancer and aging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2343.
Abstract 2344: The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma
Authors: Thomsen Martin K. 
Published: August 2019

Abstract
Activation of the STING pathway is currently being explored in cancer immune therapy. The first STING agonist tested was DMXAA, but failed in clinical trial, since it does not bind human STING. The second generation of STING agonists are cyclic di-nucleotides (CDNs), either the naturally produced 2’3’ cyclic GMP-AMP or derivatives, and many of these has proven to have high affinity for all common human variations of STING. In our work, we have focused on 3’3’-cyclic 3’3’-cAIMP (Invivogen) for analysis of anticancer activity in mice.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the incidence of HCC is increasing. We have used a mouse model of mutagen-induced HCC to explore the therapeutic usefulness of targeting the DNA-activated STING pathway in HCC. STING-deficient mice exhibited unaltered initial development of HCC, but had higher number of large tumors at late stages of disease. In the liver of STING-deficient HCC mice, we observed reduced levels of phospho-STAT1, autophagy, and cleaved caspase 3. These responses were activated in the liver by treatment with a cyclic dinucleotide (CDN) STING agonist. Importantly, CDN treatment of mice after HCC development efficiently reduced tumor size. Initiation of CDN treatment at an even later stage of disease to allow HCC detection by MR scanning, revealed that the majority of tumors regressed in response to CDN, but new tumors were detected, which were unresponsive to CDN treatment. Conclusion: modulation of the STING pathway impacts on development of HCC, and holds promise for use in treatment of this disease, most likely in combination with other immunomodulatory treatments such as PD1 inhibitors or with standard of care.
Citation Format: Martin K. Thomsen. The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2344.
Abstract 2346: Curcumin suppresses PhIP induced inflammatory protein expression in breast epithelial cells
Authors: Jain Ashok 
Published: August 2019

Abstract
PhIP (2-Amino-1-methyl-6-phenylimidazo [4,5-b] pyridine), a prominent mutagen/carcinogen is a heterocyclic amine found in meat cooked at high temperature and in tobacco. PhIP is known to induce liver, colon, skin, prostate, and breast cancer as evident from several in vivo and in vitro studies. Our previous studies have demonstrated that curcumin significantly inhibits PhIP-induced DNA adduct formation and DNA double-strand breaks with the concomitant decrease in reactive oxygen species (ROS) production via multiple molecular targets. We hypothesize that PhIP induced ROS production induces inflammatory proteins and co-treatment with curcumin would suppress the induced inflammation. Therefore, human breast epithelial cells (MCF 10A) were used to test the expression of inflammatory proteins. MCF 10A cells were treated with PhIP alone and in presence of curcumin. Untreated cells and treated only with curcumin served as control. Human Inflammation array (Ray Biotech) was used to analyze the expression of forty inflammatory proteins. Results show that the expression of twenty inflammatory proteins is induced in MCF 10 A cells when treated with PhIP as compared to the controls. Presence of curcumin reduces the induced expression of these twenty inflammatory proteins. However, three inflammatory proteins (IL-8, IL 12p40 and ICAM-1) showed a significantly higher level of expression with PhIP and curcumin co-treated cells as compared to cells treated with PhIP alone. It is shown that higher expression of IL-8, IL 12p-40 and ICAM-1 is involved in chemotactic factor involve in attracting the neutrophils, basophils; activation of T and NK cells which might be helping in coordinating the inflammation process. Hence the present study suggests that curcumin is a promising natural compound to revert the effect of PhIP induced inflammation.
Citation Format: Ashok Jain. Curcumin suppresses PhIP induced inflammatory protein expression in breast epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2346.
Abstract 235: Preclinical activity of an antibody drug conjugate targeting tumor specificmuc1 structural peptide-glycotope
Authors: Trombe Marc , Caron Anne , Tellier Alexia , Carrez Chantal , Guérif Stephane , Clavier Severine , Karst Nathalie , Saarinen Juhani , Satomaa Tero , Pitkänen Virve , Aitio Olli , Heiskanen Annamari , Fassan Matteo , Pinkas Jan , Baffa Raffaele , Blanc Veronique , Nicolazzi Celine 
Published: August 2019

Abstract
SAR566658 antibody drug conjugate (ADC) is a humanized DS6 (huDS6) antibody conjugated through a cleavable linker to the cytotoxic maytansinoid derivative DM4 that has been evaluated in the clinical setting. The purpose of our work was; 1) characterize the epitope targeted by anti DS6 on mucin1, 2) determine the prevalence of antigen expression in a patient population and 3) further explore preclinical activities of the ADC. Murine DS6 monoclonal antibody (muDS6) was generated from serous ovary adenocarcinoma immunization of immunocompetent mice. It specifically recognizes a MUC-1 tandem repeat domain in the context of cancer associated glycosylation. CA6-positive MUC-1 carries mucin-type O-linked glycans with α2,3-sialylated and β1,4-galactosylated termini, and antibody binding was abrogated by treating MUC-1 with specific glycosidases that remove either one of these glycan structures. However, the antibody did not bind to synthetic glycans modeled according to the major O-glycans of MUC-1. Our characterization of the peptide-glycotope leads us to conclude that tumor associated glycosylation is essential for the formation of the epitope on the peptide sequence of the MUC-1 tandem repeat domain. CA6 expression was evaluated by immunohistochemistry in paraffin embedded tumor tissue samples: 35.2% of breast cancer patients, 70,1% of ovarian cancer patients and 58,5% of bladder cancer patients have at least 30% of CA6 positive cells with an intensity of 2+/3+ in a multinational population-based study. In pre-clinical in vivo models, SAR566658 induced anti-tumor activity against CA6 positive tumor models of human pancreas, cervix and bladder cancer as well as and 3 Breast Patient-Derived Xenografts (PDX). Efficacy was correlated with MUC1-CA6 expression levels. In 3 additional models, SAR566658 showed anti-tumor activity that was more potent when compared to 3 conventional tubulin cytotoxic agents, docetaxel, vinorelbine and vinblastine.
Citation Format: Marc Trombe, Anne Caron, Alexia Tellier, Chantal Carrez, Stephane Guérif, Severine Clavier, Nathalie Karst, Juhani Saarinen, Tero Satomaa, Virve Pitkänen, Olli Aitio, Annamari Heiskanen, Matteo Fassan, Jan Pinkas, Raffaele Baffa, Veronique Blanc, Celine Nicolazzi. Preclinical activity of an antibody drug conjugate targeting tumor specificmuc1 structural peptide-glycotope [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 235.
Abstract 2350: Type I interferon suppresses tumor growth through activating the STAT3-granzyme B pathway in tumor-infiltrating cytotoxic T lymphocytes
Authors: Lu Chunwan , Klement John D. , Ibrahim Mohammed L. , Redd Priscilla S. , Zhou Gang , Liu Kebin 
Published: August 2019

Abstract
Type I interferons (IFN-I) have recently emerged as key regulators of tumor response to chemotherapy and immunotherapy. However, IFN-I function in immune cells in the tumor microenvironment is largely unknown. We determined that IFNα13 and IFNβ are selectively expressed in colon carcinoma tissues in vivo. Although IFNAR1 KO mice exhibited increased susceptibility to carcinogen and inflammation-induced sarcoma and colon tumorigenesis, IFNAR1-sufficient tumors grow significantly faster in IFNAR1 KO mice and in mice with IFNAR1 deficiency only in T cells, suggesting that IFN-I functions in T cells to enhance host cancer immunosurveillance. Surprisingly, unlike in an anti-viral immune response where IFN-I regulates T cell activation and clonal expansion, IFNAR1-deficient T cells exhibit no deficiency in generation of antigen-specific CTLs and IFNAR1-deficient CTLs infiltration level is similar as compared to that of WT CTLs in colon tumor-bearing mice. Gene expression profiling identified Gzmb as an IFN-I target gene in tumor-infiltrating CTLs and in antigen-specific CTLs in vivo. Mechanistically, we determined that IFN-I activates STAT3 that directly binds to the Gzmb promoter to activate Gzmb transcription in CTLs. IFN-I also regulates GZMB expression in human T cells, but IFNAR1 is not only significantly down-regulated in human colon carcinomas but also down-regulated in CTLs of human colon cancer patients as compared to normal colon and CTLs from healthy donors. Our data determined that IFN-I plays a more dominant role in CTLs than in tumor cells to execute its anti-tumor function, and doing so through activating the STAT3-granzyme B pathway in tumor-infiltrating CTLs.
Citation Format: Chunwan Lu, John D. Klement, Mohammed L. Ibrahim, Priscilla S. Redd, Gang Zhou, Kebin Liu. Type I interferon suppresses tumor growth through activating the STAT3-granzyme B pathway in tumor-infiltrating cytotoxic T lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2350.
Abstract 2355: IKKa serves as a molecular switch linking miRNA biogenesis and inflammation in skin tumorigenesis
Authors: Zhu Feng , Zhang Jian , Willette-Brown Jami , Su Ling , Wu Xiaolin , Hu Yinling 
Published: August 2019

Abstract
Our previous studies have shown that the absence of tumor suppressor IKKα leads to development of spontaneous mouse squamous cell carcinomas (SCCs) in the skin, lungs, and esophagus, which is partially mediated by aberrant epigenetic alterations and inflammation. However, it remains unknown whether there is a crosstalk between the above-mentioned mechanisms. As a part of the epigenetic machinery, miRNAs regulate many genes post-transcriptionally. Here we show that IKKα deletion in the mouse epidermis results in impaired miRNA processing with markedly reduced expression of ribonuclease Dicer, an enzyme required for miRNA maturation. We found that the lack of IKKα causes Dicer gene silencing through DNA methylation. As a result, the maturation of miR-203-3p, which is the most abundant miRNA in keratinocytes, is blocked in Ikkα-null keratinocytes. Next, we identified Myd88, an important component of innate immunity and inflammation, as one of miR-203-3p targets. The level of Myd88 expression is robustly increased in Ikkα-null keratinocytes due to the lack of miR-203-3p. We also observed increased activity of caspase 1 cleavage, an indicator of inflammasome activation, in Ikkα-null keratinocytes. Interestingly, Myd88 deletion or 5-aza-2’-deoxycytidine (DNA methyltransferase inhibitor) treatment rescued the survival of Ikkαf/f;K5Cre mice, which usually die within three weeks after birth. Ikkαf/f;Myd88f/f;K5Cre mice also develop much fewer spontaneous skin tumors. By analyzing a cohort of human head and neck SCCs from TCGA database, we found that Dicer expression is concurrently downregulated among 32% of patients with low IKKα expression. Taken together, our finding illustrated how IKKα loss mediates Dicer gene silencing, which turns off miRNA processing, including miR-203-3p maturation, and eventually triggers Myd88-dependent inflammation. Thus, our study revealed a novel IKKα/Dicer/miR-203-3p/Myd88 signaling loop, in which IKKα serves as a molecular switch linking microRNA biogenesis and inflammation in skin tumorigenesis.
Citation Format: Feng Zhu, Jian Zhang, Jami Willette-Brown, Ling Su, Xiaolin Wu, Yinling Hu. IKKa serves as a molecular switch linking miRNA biogenesis and inflammation in skin tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2355.
Abstract 2357: Identification of microRNAs associated with melanoma immunity and immunotherapy outcome
Authors: Sloane Robert A. Szczepaniak , Andrews Miles C. , Han Guangchun , Haydu Lauren , Burton Elizabeth , Jeffrey Gershenwald E. , Davies Michael A. , Wang Linghua , Woodman Scott , Wargo Jennifer 
Published: August 2019

Abstract
Introduction:Resistance to immunotherapy is a significant clinical challenge, preventing or limiting response to PD1 checkpoint blockade in approximately 60% of melanoma patients. We sought to identify microRNAs (miRs) that modulate the tumour immune microenvironment and potentially influence outcome to immunotherapy.Methods:To identify miRs associated with immune infiltration and exclusion in melanoma, we first compared miR expression in the human skin cutaneous melanoma (SKCM) dataset from The Cancer Genome Atlas (TCGA) with a selection of immune correlates including histologic assessment of tumour infiltrating lymphocytes (TIL), gene expression-based cytolytic score using Granzyme A and Perforin 1, and transcriptomic estimation of immune cell populations using CIBERSORT. In parallel, we performed miR sequencing of 22 pre-PD-1 inhibitor treatment melanoma tumors to identify differentially-expressed miRs according to PD-1 inhibitor response. We then tested the immune effects of candidate immunomodulatory miRs using microRNA mimics in a panel of human melanoma cell lines, evaluating immunomodulatory cytokine secretion using a bead-based immunoassay (LEGENDplex) and cell surface expression of HLA-A and PD-L1 by flow cytometry.Results:We identified 14 microRNAs associated with immune infiltration or exclusion in the TCGA melanoma dataset. In vitro characterisation of these miRs showed that they regulate secretion of IL-6 and VEGF, and expression of HLA-A in human melanoma cell lines. Furthermore, we identified 25 downregulated and 8 upregulated miRs in responder vs non-responder melanoma lesions (log2 fold change &gt;=1, padj&lt;0.1), including several miRs with high-confidence targets involved in oncogenesis, cancer germline antigens and modification of the extracellular matrix that may impact upon susceptibility to immune attack.Conclusions:This study identified several immunomodulatory miRs associated with immune infiltration in melanoma tumors of TCGA. Several of these candidate immunomodulatory miRs show evidence of activity relevant to the efficacy of PD-1 checkpoint blockade, whilst additional response/resistance-associated miRs were identified. These miRs represent strong candidates for ongoing in vitro and in vivo studies in combination with immunotherapy.
Citation Format: Robert A. Szczepaniak Sloane, Miles C. Andrews, Guangchun Han, Lauren Haydu, Elizabeth Burton, Gershenwald E. Jeffrey, Michael A. Davies, Linghua Wang, Scott Woodman, Jennifer Wargo. Identification of microRNAs associated with melanoma immunity and immunotherapy outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2357.