Tumor & microenvironment最新文献

{"title":"Tumor Microenvironment: Molecular Players – Part A","authors":"Wim E. Crusio, J. Lambris, Alexander Birbrair","doi":"10.1007/978-3-030-43093-1","DOIUrl":"https://doi.org/10.1007/978-3-030-43093-1","url":null,"abstract":"","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89463430","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 C108: Systematic identification of astrocyte-tumor crosstalk regulating brain metastatic tumors","authors":"Haowen Liu, J. Sheng, Hong Zhao, Stephen T C Wong","doi":"10.1158/1535-7163.targ-19-c108","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-19-c108","url":null,"abstract":"","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74567932","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 PR11: Hyperspectral imaging tools capture the spatial organization of cell subsets within the tumor microenvironment","authors":"Katey S. S. Enfield, Spencer D. Martin, Sonia H Y Kung, P. Gallagher, C. MacAulay, M. Guillaud, W. Lam","doi":"10.1158/1557-3265.AACRIASLC18-PR11","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-PR11","url":null,"abstract":"Immune cells are a major component of the tumor microenvironment (TME). The spatial organization of immune cell subpopulations within the TME is recognized to have biologic significance and clinical relevance. For example, spatial organization of immune cell subsets within the TME is critical for the inhibition of cytotoxic T-cell activity through direct interaction of ligand (PD-L1) with receptor (PD-1)). However, precise spatial deconvolution is limited by the lack of imaging algorithms for in situ multiplex single cell analyses as flow cytometry does not preserve data in the spatial dimension. To this end, we have developed a hyperspectral imaging platform designed for analyzing multichannel immunohistochemical-stained tissue sections for generating cell density data and reconstructing spatial architecture for tumor biology as well as clinical association studies. Whole-tissue sections from 20 lung adenocarcinomas with at least 5 years’ follow-up were stained for CD3 (pan-T cell), CD8 (cytotoxic T cell), and CD79a (B cell and plasma cell) and counterstained with hematoxylin. Multispectral images were acquired for five fields of view and analyzed to quantify cell types. Regions of Interest (ROIs) were then identified and analyzed in order to quantify cell-cell spatial relationships. Nonrandom patterns of immune cell distributions were identified using the Monte Carlo resampling method (500 iterations). Cell counts, densities, spatial relationships, and significant immune cell distributions were associated with clinical features (Kruskal - Wallis p Our analysis generated 234 image files for analysis, with an average of 16,400 cells per image. The densities of intratumoral CD8+ cytotoxic T cells were significantly higher in nonrecurrent cases, agreeing with literature reports. Similarly, cell sociology deductions identified relationships associated with metastasis: tumor cells in nonmetastatic cases had increased numbers of CD8+ cytotoxic T-cell neighbors. Following Monte Carlo analysis, nonrandom cell~cell spatial proximities emerged that were not identified at a cell density level. We have developed a hyperspectral imaging platform capable of quantifying cell-cell spatial relationships within tissue sections. This technology can be applied to larger clinical cohorts for the study of therapeutically targetable immune cell subsets with the goal of identifying patterns that correlate with clinical response and patient outcome. This abstract is also being presented as Poster B16. Citation Format: Katey S.S. Enfield, Spencer D. Martin, Sonia H.Y. Kung, Paul Gallagher, Calum E. MacAulay, Martial Guillaud, Wan L. Lam. Hyperspectral imaging tools capture the spatial organization of cell subsets within the tumor microenvironment [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79569719","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 B46: Roles for LKB1 at the immune synapse during B-cell activation and antitumor responses","authors":"L. Jimenez, Lynnea R. Waters, Diane N. H. Kim, N. Walsh, M. Teitell","doi":"10.1158/2326-6074.TUMIMM17-B46","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B46","url":null,"abstract":"Defense from infection or cancer is provided by coordinated actions of the innate and adaptive immune system, including B lymphocytes that generate antibodies (Abs) against pathogens or tumor antigens. B cells establish immune synapses with antigen-presenting cells during activation to initiate Ab-production, which may include entrance into a germinal center (GC) reaction to generate very high-affinity Abs. Establishment of an immune synapse requires polarity proteins to coordinate uptake and processing of external antigens. For this, there is a highly conserved family of partitioning defective (Par) proteins that mediates cell polarity in multiple cell types. In particular, Par-3, a member of the Par polarity complex (Par-3, aPKC, Par-6), is a key protein that localizes to the immune synapse and is required for B cell polarization and immune synapse formation. Recently, we showed that LKB1, the mammalian homolog of Par-4 and a regulator of energy metabolism, controls B cell activation, GC formation and differentiation into Ab-producing plasma cells. However, roles for LKB1 in B cell polarity, immune synapse formation and anti-tumor immunity are unknown. Based on previous studies showing that LKB1 induces cell polarity and co-localizes with Par-3, we hypothesize that LKB1 is required for Par complex assembly and controls immune synapse formation during B cell activation. Subcellular analysis of LKB1 by immunofluorescence microscopy in mouse primary B cells reveals LKB1 co-localization with aPKC in membrane protrusions required for immune synapse formation. Interestingly, B cell specific LKB1 knock out (BKO) mice exhibit mislocalization of aPKC/Par complex, loss of lymphoid tissue polarity and spontaneous B cell activation that results in the formation of giant GCs and secretion of proinflammatory cytokines and chemokines. Similar inflammatory profiles with T cell chemoattractants are known to recruit CD8+ cytotoxic T lymphocytes (CTLs) into solid tumors, such as melanoma. These similarities suggest that LKB1 inactivated B cells in the tumor microenvironment could stimulate T cell infiltrates into solid tumors. Our studies suggest that physiologic inactivation of LKB1 in B cells controls B cell activation, GC formation and potentially infiltration of T cells in the tumor microenvironment during anti-tumor responses. We are currently utilizing an exciting genetic mouse melanoma model to examine the role of LKB1 in promoting anti-tumor immunity. Together, our studies assess LKB1 as a target for augmenting adaptive immunity against cancer. Citation Format: Laura Jimenez, Lynnea Waters, Diane N.H. Kim, Nicole Walsh, Michael A. Teitell. Roles for LKB1 at the immune synapse during B-cell activation and antitumor responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B46.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90892411","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 B32: Microfluidics to study solid tumor-NK cell interactions: From migration and cytotoxicity to therapeutic antibodies","authors":"J. Ayuso, Regan Truttschel, Max M Gong, Mouhita Humayun, A. Gillette, M. Patankar, M. Skala, D. Beebe","doi":"10.1158/2326-6074.TUMIMM17-B32","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B32","url":null,"abstract":"Introduction: Solid tumors develop a complex microenvironment; that enables immune surveillance escape. In solid tumors, cancer cells form a dense mass where antibody and immune cell penetration is significantly hindered. Additionally, tumor cell metabolism leads to hypoxia, nutrient starvation and acidic pH; that dampens immune response. Therefore, to translate the success of immunotherapies in hematological cancers to solid tumors; there is need for new in vitro models that recapitulate this complex tumor microenvironment (TME). In this context, microfluidics offers an opportunity to generate sophisticated in vitro systems, combining multiple cell types and capturing in vivo spatial organization. Here, we present a microfluidic model that mimics the TME of solid tumors and apply it to study adoptive immunotherapies and therapeutic antibodies. Materials and Methods: In our model, a spheroid of MCF7 breast cancer cells was embedded in a 3D collagen I matrix. Multiple luminal structures were generated through the matrix adjacent to the spheroid and lined with endothelial cells (e.g., HUVECs, IPSC-EC) to form blood vessels. Activated immune cells (e.g., NK-92 cells) and/or therapeutic antibodies (e.g., IL-2 conjugated anti-EpCAM) were perfused through these blood vessels. Antibody diffusion, cell migration and cytotoxicity were subsequently measured by fluorescence and confocal microscopy. Results and Discussion: A small percentage of NK cells extravasated from the blood vessel into the matrix. Once within the extracellular matrix, NK cells exhibited rapid migration; however, we did not observe a directional response towards the tumor spheroid. In fact, the NK cells that reached the spheroid followed a random, tortuous path. Taken together, these initial results point out that immune extravasation and “homing” (i.e., the capacity to track and migrate towards tumor cells) could be engineered to improve treatment efficacy. After several days in culture, the presence of NK cells induced significant cytotoxicity in the MCF7 spheroid. NK cell-mediated cytotoxicity occurred at the surface of the tumor spheroid; whereas tumor cells in the core remained unaffected. Different therapeutic antibody formulations were perfused through the adjacent lumen to enhance NK-mediated cytotoxicity. Fluorescently-labelled antibodies diffused through the blood vessel, reaching and coating the surface of the spheroid in a few hours. However, penetration of the core was dramatically slower; after 3 days, only the most outer cell layers of the spheroid were stained. The antibody remained attached to the tumor cell membrane for multiple days, showing no signs of internalization. Therefore, this model could be used to study the efficacy of antibody-dependent therapy, in particular, short and repeated cycles of antibody/immune cell injection. Conclusion: The TME can dramatically limit the immune response against solid tumors. The presented microfluidic model was used to study N","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73542587","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 PR07: Role of the microbiota in inflammation and lung cancer","authors":"A. Robles, T. Cooks, Eleazar Vega-Valle, Marie Vetizou, Uriel Rose, A. Miyanaga, Akriti Trehan, T. Oike, B. Ryan, S. Sen, L. Greathouse, G. Trinchieri, C. Harris","doi":"10.1158/1557-3265.AACRIASLC18-PR07","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-PR07","url":null,"abstract":"We recently conducted the first comprehensive characterization of the lung cancer microbiome, utilizing 16S rRNA gene sequencing of lung tissue from controls and cancer cases, with validation by metagenomics analysis of RNA-seq unmapped reads from lung cancer samples in The Cancer Genome Atlas. Evidence from 16S rRNA and metagenomics analysis indicated that specific bacteria are associated with the development of lung cancer in humans. However, the functional role of bacteria in the inflammatory microenvironment of the lung and the incidence and progression of lung cancer is unknown. Cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. We hypothesized that lung colonization with selected bacterial strains will affect the immune microenvironment and accelerate the rate of tumor development in an autochthonous mouse model of lung cancer. Specifically, we focused on Acidovorax , a taxon we found to be enriched in lung squamous cell carcinoma (SCC) from smokers and with TP53 mutations. Kras LSL-G12D/+ and Trp53 LSL-R172H/+ mice (KPC mouse model), conditionally expressing oncogenic Kras and a gain-of-function mutant p53 (a combination of mutations commonly found in human lung cancer), were exposed to Acidovorax temperans via intranasal delivery. Two weeks after exposure to 5 x 10 6 PFU Ad-Cre (specifically activating the conditional alleles in the lungs), mice were randomly assigned to treatment groups. A biweekly intranasal instillation of 10 9 CFU Acidovorax temperans (ATCC #49666) was administered in PBS and compared with a sham treatment (PBS alone) for a total of six instillations. One week after the last bacteria instillation (13 weeks after Ad-Cre treatment), mice were subjected to magnetic resonance imaging (MRI). We found a significant increase in tumor volume in animals inoculated with Acidovorax temperans as compared to sham-treated animals (p=0.03), and increased lung weight as a percent of total body weight. To delineate the interactions between the bacteria and the immune system of the host, we co-cultured Acidovorax temperans with human primary macrophages. Our findings show that when Acidovorax temperans is engulfed by M2-like macrophages, the phagocytotic activity of the macrophages is attenuated. In addition, when T cells were co-cultured with M2 macrophages pre-exposed to Acidovorax temperans , their cytotoxicity was inhibited. This inhibition was governed by the CD47-SIRPα “Don’t eat me” signal. These preliminary data indicate that Acidovorax temperans contributes to lung tumorigenesis in the presence of activated Kras and mutant p53. We are conducting additional experiments to investigate the specificity of this observation with respect to Acidovorax temperans and to better understand the role of the microbiota in cancer initiation and progression. This abstract is also being presented as Poster B19. Citation Format: Ana I. Robles, Tomer Cooks, El","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75274020","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 B30: Three-dimensional organoid model for acquired drug resistance in non-small cell lung cancer","authors":"Navika D. Shukla, A. Salahudeen, S. Padda, J. Neal, H. Wakelee, C. Kuo","doi":"10.1158/1557-3265.AACRIASLC18-B30","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-B30","url":null,"abstract":"Background: Targeted therapies against specific driver mutations of cancer progression have been used to improve survival of lung adenocarcinoma patients. In KRAS mutant NSCLC specifically, however, after some initial improvement in lung cancer patients, targeted therapies often fail due to acquired drug resistance. To uncover mechanisms of resistance and to discover new drivers, genome-scale sequencing of lung cancers has identified candidate genes, but these data have not rapidly translated in preclinical validation. A major obstacle in lung cancer research has been the deficiencies of standard in vitro models. Methods: To address the deficiencies within standard models we have developed an in vitro 3-dimensional, KRAS-mutated “organoid” model of lung adenocarcinoma that surpasses both in vitro and in vivo models by possessing the tractability of cell lines and the 3-dimensional architecture and morphology of animal models. We have engineered a p53 knockout and KRAS mutation on top of normal wild-type lung epithelium to achieve oncogenicity. Result: Through an optimized growth period in the presence of drug, an organoid model of resistance has been developed through which de novo genetic events underlying acquired resistance can be studied. Conclusion: The highly defined genetic background of the KRAS-mutated 3-D organoid model serves as a tabula rasa upon which stochastic secondary genetic and epigenetic changes can be identified and mechanistically studied by forward and reverse genetics approaches in order to rapidly identify mechanisms of acquired drug resistance and validate therapeutic options. Citation Format: Navika D. Shukla, Ameen A. Salahudeen, Sukhmani K. Padda, Joel W. Neal, Heather A. Wakelee, Calvin J. Kuo. Three-dimensional organoid model for acquired drug resistance in non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B30.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"67 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81157371","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 B30: Digital multiplex immunofluorescence analysis identifies immune profiles in the tumor stroma associated with clinical outcome","authors":"A. Mezheyeuski, C. Bergsland, M. Backman, T. Sjöblom, R. Lothe, J. Bruun, P. Micke","doi":"10.1158/2326-6074.TUMIMM17-B30","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B30","url":null,"abstract":"Background: The recent successes of immunotherapy in non-small cell lung cancer (NSCLC) raise the interest to the deeper understanding of the diversity of the immune microenvironment. Meticulous characterization of the immune cell infiltrates is crucial for patients’ prognosis and the prediction therapeutic effects. The aim of this study was to analyze expression profiles of the immune cells and their linkage to clinical parameters in NSCLC patients. Methods: A tissue microarray of the NSCLC cohort comprised of 55 cases was used in the study. The staining was performed with the antibodies against CD8, CD20, CD4, FoxP3, CD45RO and pan-cytokeratin together with immuno-fluorescent markers (Opal, Perkin Elmer) and digital images acquired by a multispectral imaging system (Vectra 3, PerkinElmer). Marker expression pattern was evaluated on a cell level in total sample area, or in stroma and tumor area separately. Conventional immunohistochemical techniques and RNAseq data were used to validate the method. Results: Marker expression intensities were used to identify 5 non-epithelial cell classes, which express CD8, CD20, CD4, FoxP3, CD45RO. Relative abundance of marker-positive cells in individual cases were subjected to hierarchical clustering analysis, for the discovery of distinct immune cell infiltration patterns. The resulted clusters were exploratively analyzed with regard to survival associations. Patients with specific immune profile with high infiltration of FoxP3+ cells, moderate infiltration of CD4+ and CD8+ cells and low quantity of CD20+ and CD45RO+ cells in the stroma were associated with longer survival (median 87 vs. 54 month, log-rank p=0.050). Conclusion: Multi-marker analysis on single-cell levels with the fluorescence multiplexed IHC technique provides a valuable basic immune profile of cancer patients. Clustering analysis of the expression of immune markers identified a group of patients with improved survival in NSCLC independent of histology. Note: This abstract was not presented at the conference. Citation Format: Artur Mezheyeuski, Christian Bergsland, Max Backman, Tobias Sjoblom, Ragnhild A. Lothe, Jarle Bruun, Patrick Micke. Digital multiplex immunofluorescence analysis identifies immune profiles in the tumor stroma associated with clinical outcome [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B30.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84852816","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 B53: Intra-tracheal delivery of low-dose bacterial lipopolysaccharides protects against tumor formation in the KP lung adenocarcinoma model","authors":"G. Sriram, Lauren E. Milling, D. Irvine, M. Yaffe","doi":"10.1158/2326-6074.TUMIMM17-B53","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B53","url":null,"abstract":"While genetically engineered mouse models (GEMM) of lung adenocarcinoma (LUAD) recapitulate some aspects of the histopathology of human LUAD, they poorly reflect the inflammatory components of human LUAD. In this study, we performed repeated weekly intra-tracheal dosing with bacterial lipopolysaccharides (LPS) after adenoviral-Cre (AdCre) delivery into K-RasLSL-G12D/+; p53fl/fl mice to examine the effect of inflammation on lung adenocarcinoma progression. LPS has been historically used to study the acute inflammatory response both locally and systemically in animal models. The typical response involves recruitment and activation of innate immune cells, mainly neutrophils and macrophages, to the site of delivery and/or production of pro-inflammatory cytokines including TNF-alpha, IL-6 and IL-1. Repeated long-term conditioning with low-dose LPS results in alveolar wall thickening as observed by uCT and the accumulation of lymphoid aggregates in the lung. However, surprisingly, LPS conditioning drastically reduced tumor incidence from 75% in the control group to 25%. Furthermore, starting LPS delivery four weeks after AdCre instillation, to eliminate any possible LPS effects on adenoviral delivery and K-Ras induction/p53 loss, still resulted in drastically reduced lung tumor formation suggesting that the effect results from an LPS-induced immune response. Two LPS instillations were sufficient to elicit this effect. Short-term antibody-mediated depletion of neutrophils or CD8+ T cells also did not abrogate the effect of LPS on tumor formation. In vitro re-stimulation of CD8+T cells (from blood or spleen) from tumor-free animals with KP tumor cells did not elicit interferon-gamma production, as assayed by intra-cellular cytokine staining and ELISPOT, suggesting that a cell type other than CD8+ T-cells or neutrophils mediates the effect. Interestingly and consistent with the inhibitory effect of LPS on tumor formation, multiple pneumonia diagnoses in COPD patients/smokers has been associated with a lower odds ratio of developing lung cancer in humans. Identifying the cell-type (s) and mechanisms mediating the anti-tumor effect of LPS will help in defining the aspects of immune response that inhibit LUAD progression. Citation Format: Ganapathy Sriram, Lauren Milling, Darrell J. Irvine, Michael B. Yaffe. Intra-tracheal delivery of low-dose bacterial lipopolysaccharides protects against tumor formation in the KP lung adenocarcinoma model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B53.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"154 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86270779","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 B17: Interleukin-17 and -22 expression in non-small cell lung cancer","authors":"J. Stump, Yue Jiang, C. Karches, J. Gosálvez, J. Neumann, S. Kobold, R. Hatz, H. Winter, A. Tufman, R. Huber, S. Reu","doi":"10.1158/1557-3265.aacriaslc18-b17","DOIUrl":"https://doi.org/10.1158/1557-3265.aacriaslc18-b17","url":null,"abstract":"Background: In non-small cell lung cancer (NSCLC) the TNM staging remains standard for prognostic assessment and therapy decisions. Nevertheless, stage-specific outcomes vary significantly, indicating a need for additional prognosticators. In this retrospective study we wanted to assess the role of the mediator interleukin-22 (IL-22), as IL-22 is known to be involved in various lung diseases and to be elevated in lung cancer patients. Moreover, we evaluated interleukin-17 (IL-17), which also depicts a proinflammatory cytokine, but seems to play a dual role in antitumor immunity. We asked the question of their link to prognosis, therapy response and recurrence. Methods: Tissue microarrays (TMAs) were generated from formalin-fixed, paraffin embedded tissue of 138 curatively resected patients with stage IA-IV NSCLC. TMAs included each three cores from the tumor center (CT) and invasive margin (IM), selected from areas with the most dense lymphocytic infiltrates. IL-22 and IL-17 expression of the tissue was analyzed by immunohistochemistry via cytoplasmic staining (double-staining: IL-22, CD3 resp. IL-17, CD3). Results: IL-22 expression status in adeno and SCC does not seem to have a prognostic impact on survival, regardless of the localization. However, a high IL-22 CT/IM ratio in adenocarcinoma is clearly linked to longer overall survival; this cannot be seen in SCC. For IL-17 a distinct tendency is visible for adeno and SCC in the invasive margin as well as in the tumor center—interestingly, this is more clear for SCC. In SCC a high CT/IM ratio for IL-17 seems to have a positive prognostic impact on overall survival. Patient numbers will be enlarged to validate these findings. Conclusion: The cytokines IL-22 and IL-17 seem—depending on histology and location—to have a prognostic impact on overall survival in NSCLC. In previous experiments we showed that multispectral assessment of CD8 and PD-L1 has a clear correlation with clinical outcome. Adding cytokines to this method might open novel avenues for predicting clinical outcome and therapeutic efficacy in NSCLC. Citation Format: Julia Stump, Yue Jiang, Clara Karches, Javier Suarez Gosalvez, Jens Neumann, Sebastian Kobold, Rudolf Hatz, Hauke Winter, Amanda Tufman, Rudolf M. Huber, Simone Reu. Interleukin-17 and -22 expression in non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B17.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90332818","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}