Tumor & microenvironment最新文献

{"title":"Abstract IA34: Targeting cellular heterogeneity in lung adenocarcinoma","authors":"N. Marjanovic, Matan Hofree, David A. Canner, M. Trakala, Katherine Wu, Olivia C. Smith, Jonathan Y. Kim, A. Amon, A. Regev, T. Jacks, T. Tammela","doi":"10.1158/1557-3265.AACRIASLC18-IA34","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-IA34","url":null,"abstract":"Cancer arises from a single cell through a series of acquired mutations, and gradually develops into a complex tissue comprising phenotypically heterogeneous societies of cancer cells. The phenotype, or state, of each tumor cell is influenced by multiple cell-autonomous and cell-extrinsic factors; the diversity of these cellular states poses a challenge for effective cancer therapies. We characterized the evolution of transcriptomes at the single-cell level in genetically engineered murine lung tumors driven by oncogenic Kras. Tumor progression was accompanied by a dramatic increase in cellular heterogeneity, which was further exacerbated upon deletion of the p53 tumor suppressor, allowing tumor progression into advanced adenocarcinomas. This heterogeneity was manifested by the emergence of de-differentiated or transdifferentiated populations, the activation of latent developmental or regenerative programs, as well as heterogeneous activation of signaling pathways. Surprisingly, similar heterogeneous populations emerged in independent tumors irrespective of considerable intertumoral differences in genetic copy number alterations, suggesting a remarkable degree of convergence to achieve a common evolutionary endpoint. We used these data to computationally model cell-state transitions. Finally, treatment of the lung tumors with chemotherapy enabled the identification of cellular states associated with intrinsic sensitivity or resistance. These results associate tumor progression with increasing transcriptional heterogeneity. The identification of unique gene expression programs in cancer cell subpopulations provides a path towards reducing cellular heterogeneity in cancer. Citation Format: Nemanja Marjanovic, Matan Hofree, David Canner, Marianna Trakala, Katherine Wu, Olivia Smith, Jonathan Kim, Angelika Amon, Aviv Regev, Tyler Jacks, Tuomas Tammela. Targeting cellular heterogeneity in lung adenocarcinoma [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 IA34.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"30 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72461294","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 B73: Pleiotrophin drives a pro-malignant macrophage phenotype in preclinical models of breast cancer","authors":"Kristi D. Lynn, Adrian T. A. Dominguez, E. Berens, J. Toombs, A. Wellstein, R. Brekken","doi":"10.1158/2326-6074.TUMIMM17-B73","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B73","url":null,"abstract":"Tumor-associated macrophages promote progression to malignancy, metastasis, and resistance to chemotherapy in breast and pancreatic cancer. Furthermore, macrophage recruitment in tumors correlates with a worse prognosis in breast cancer patients. The phenotype of tumor associated macrophages is influenced by many factors, including the cytokine milieu within the tumor. We have identified a population of macrophages in genetic models of breast cancer that express Vascular Endothelial Growth Factor Receptor 2 (Vegfr2). Using flow cytometry and immunohistochemical analyses, we found that this population is enriched for markers associated with macrophages that promote angiogenesis, immune suppression, and metastasis. In vitro, we identified the heparin-binding peptide, pleiotrophin (PTN), as a candidate cytokine that induces Vegfr2 and anti-inflammatory cytokine expression by macrophages. Additionally, we found that PTN-stimulated macrophages can greatly increase cancer cell migration in vitro. In the MMTV-PyMT transgenic murine model of breast cancer, we observed that expression of PTN correlates with levels of Vegfr2+ macrophages and progression to malignancy. Crizotinib, an inhibitor of the pleiotrophin receptor, Anaplastic Lymphoma Kinase, reduced anti-inflammatory and Vegfr2+ macrophages in vivo. This decrease was concomitant with a significant reduction in pulmonary metastasis. This finding was corroborated by the use of 3B10, a neutralizing pleiotrophin monoclonal antibody. The potential impact of this work includes identifying a novel biomarker of promalignant macrophages, a therapeutic strategy to target them, and developing a deeper understanding of the function of macrophages in metastasis. Citation Format: Noah Sorrelle, Kristi D. Lynn, Adrian TA Dominguez, Eric Berens, Jason E. Toombs, Anton Wellstein, Rolf A. Brekken. Pleiotrophin drives a pro-malignant macrophage phenotype in preclinical models of breast cancer [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 B73.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84301781","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 B13: The impact of combined CDK9 inhibition and TRAIL treatment on NSCLC","authors":"Itziar Areso Zubiaur, A. Montinaro, S. Karstedt, J. Lemke, T. Hartwig, Lucia Taraborelli, S. Surinova, M. El-Bahrawy, H. Walczak","doi":"10.1158/1557-3265.aacriaslc18-b13","DOIUrl":"https://doi.org/10.1158/1557-3265.aacriaslc18-b13","url":null,"abstract":"Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to specifically kill cancer cells in vivo. On the basis of this, TRAIL-receptor (TRAIL-R) agonists were devised for clinical use. However, to date, TRAIL-R agonists have only shown limited therapeutic benefit in clinical trials. This can most likely be attributed to the fact that most primary human cancers are TRAIL resistant. It is therefore important to identify potent and cancer-selective TRAIL-sensitizers that overcome TRAIL resistance. Recently, the combination of CDK9 inhibition with TRAIL was found to effectively induce apoptosis in a panel of TRAIL-resistant non-small cell lung cancer (NSCLC) cell lines. Furthermore, tumors from NSCLC patients show high expression levels of CDK9, providing a rationale for targeting CDK9 in lung cancer. Here, we evaluate how effective the new TRAIL/CDK9 inhibition combination therapy is in treating lung cancer in an autochthonous mouse model (the KrasG12D/p53R172H) that closely recapitulates the human disease. We found that this combination was highly effective in vivo and led to a significant tumor regression and prolonged the survival of these mice. Our most recent results regarding these effects will be presented. Citation Format: Itziar Areso Zubiaur, Antonella Montinaro, Silvia von Karstedt, Johannes Lemke, Torsten Hartwig, Lucia Taraborelli, Silvia Surinova, Mona A. El-Bahrawy, Henning Walczak. The impact of combined CDK9 inhibition and TRAIL treatment on NSCLC [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 B13.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73240269","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 B63: Bittersweet symphony: How tumor-associated glycan structures orchestrate immune evasion","authors":"L. Cornelissen, Athanasios Blanas, Joost C. Van der Horst, L. Kruijssen, Y. Kooyk, S. J. Vliet","doi":"10.1158/2326-6074.TUMIMM17-B63","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B63","url":null,"abstract":"The tumor microenvironment is immune suppressive, allowing tumor cells to escape from immune attack. By relieving this immune suppression, immune cells might be able to effectively eliminate the tumor. Therefore, a detailed understanding on how tumor cells induce an immunosuppressive tumor microenvironment is required. Glycosylation is the most abundant post-translational modification of proteins. It is highly diverse on a cellular level and strongly affected by oncogenesis. Tumor cells generally display an aberrant glycosylation profile and this is now well accepted as a new hallmark of cancer. Overexpression of glycan structures containing sialic acids (Sia) is frequently observed on tumors. Glycan structures can be recognized by lectin receptors expressed on immune cells, whereby sialic acids specifically bind to the Siglec receptor family. The majority of Siglec receptors has an immunoreceptor tyrosine-based inhibition motif and therefore, sialylated glycan structures are known to suppress ongoing immune responses. Hence, we hypothesize that tumor cells overexpress sialylated glycan structures in order to communicate with the immune system and to dampen immune attack. We have previously demonstrated that a genetically engineered Sialow glycovariant of the mouse melanoma B16 model displayed delayed growth in vivo compared to wild-type B16 Siahigh tumors (1). Moreover, higher frequencies of IFNγ-producing effector T-cells were detected in B16 Sialow tumors. This was paralleled by a 50% reduction in FoxP3+CD4+ regulatory T-cell frequencies in Sialow tumors (1), together indicating that tumor-associated sialic acids indeed play, indeed, a crucial role in suppressing the anti-tumor immune response. To check whether the inhibitory effect of sialic acids on the effector T cell response is tumor type specific, we investigated the role of sialic acids in a mouse colorectal cancer model (MC38). With the use of Crispr-Cas9 we successfully knocked out the N-acylneuraminate cytidylyltransferase (CMAS) gene, which is responsible for the sialylation pathway and thus the generation of sialylated glycans on the cell surface. In contrast to the B16 Sialow tumors, the Sianeg MC38 CMAS KO tumors displayed an increased tumor growth in vivo compared to the Siahigh MC38 Mock tumors. Moreover, less viable leukocytes could be recovered from the Sianeg MC38 CMAS KO tumors compared to the Siahigh MC38 Mock tumors. With the use of mass spectrometry, we analyzed the complete glycosylation profile of our Sianeg MC38 CMAS KO and Siahigh MC38 Mock cells and observed, in addition to the absence of sialylation, an increase in LacNAc (Galβ1-4GlcNAc) structures on the Sianeg MC38 CMAS KO cells. This glycan structure is a ligand for carbohydrate-binding Galectin receptors. Galectins are well known for their potential to induce leukocyte apoptosis after binding specific glycoproteins on the leukocyte surface. Using qPCR we observed higher mRNA levels of Galectin-1 in our MC38 CMA","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74731875","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 B56: CXCR2 blockade reduces granulocytic myeloid cell compensation in response to macrophage targeted therapy and further enhances the efficacy of chemotherapy in pancreatic ductal adenocarcinoma","authors":"B. Han, T. Nywening, B. Belt, Jian Ye, W. Hawkins, D. DeNardo, D. Linehan","doi":"10.1158/2326-6074.TUMIMM17-B56","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B56","url":null,"abstract":"Background: The incidence of pancreatic ductal adenocarcinoma (PDAC) is rising, yet patient survival rates following conventional treatment remain abysmal. A unique feature of PDAC is the presence of a prominent tumor stroma with a dense network of fibrotic material and abundant inflammatory immune infiltrate. Bone marrow derived myeloid cells of both monocytic and granulocytic origin, including tumor associated macrophages (TAM) and neutrophils (TAN) respectively, are the most prevalent immune cells in the tumor microenvironment (TME) of PDAC. PDAC tumors co-opt chemokine signaling pathways to attract myeloid cells from the bone marrow to the TME where they suppress anti-tumor immune responses, support tumor progression, and confer resistance to therapy. In a previous clinical study, we demonstrated that targeted blockade of CCR2+ TAM with a small molecule CCR2 inhibitor (PF-04136309) nearly doubled responses to the FOLFIRINOX chemotherapy regimen in patients with locally advanced PDAC. Here, we show that tumor infiltrating CXCR2+ TAN compensate for TAM depletion in response to CCR2 blockade, so we hypothesized that dual targeting of both CCR2+ TAM and CXCR2+ TAN would further enhance chemotherapy efficacy for treating PDAC. Methods: Human blood, bone marrow, and tumor samples were acquired under an IRB approved protocol. PDAC cell lines (KCKO or KP) derived from spontaneous tumors were subcutaneously or orthotopically implanted into C57BL/6 mice. Tumor bearing mice were randomized and treated with vehicle, FOLFIRINOX, CCR2i (PF-04136309 or RS504393), CXCR2i (SB225002), CCR2i+CXCR2i, CCR2i+FOLFIRINOX, CXCR2i+FOLFIRINOX, or CCR2i+CXCR2i+FOLFIRINOX. Mice were sacrificed at fixed time points for tissue collection or followed for survival. Resected tissues were snap frozen for RNA extraction to perform qRT-PCR, fixed in formalin for histological staining and immunohistochemistry, or digested into single cell suspensions for flow cytometry analysis. Results: The prevalence of peripheral blood and bone marrow CXCR2+ TAN is prognostic in patients with PDAC. Tumors expressed elevated levels of the ELR+ chemokines including CXCL1, CXCL2, CXCL5, and CXCL8 and were infiltrated with significantly more CXCR2+ TAN compared to normal pancreas. Tumor expression of the ELR+ chemokines correlated with tumor infiltrating TAN and their levels were prognostic in human disease. Analysis of longitudinally paired tumor biopsies from patients treated with PF-04136309 had significantly increased levels of CXCR2+ TAN (p Conclusions: The ELR+ CXC/CXCR2 chemokine pathway plays a key role in PDAC tumor progression and CXCR2+ TAN compensation is observed with depletion of TAM in response to CCR2 blockade. Duel targeting of CCR2+ TAM and CXCR2+ TAN prevents myeloid plasticity to single agent therapy and further enhances the efficacy of chemotherapy. Thus, further studies exploring complementary immune targeting strategies are warranted in PDAC. Citation Format: Booyeon J. Han,","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80106408","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 B25: Decoding tumor microenvironment to enhance NSCLC targeted therapy","authors":"Haichuan Hu, L. Sequist, Z. Piotrowska, Hillary E. Mulvey, Sundus Noeen, Patricia J. Hare, D. Kodack, A. Hata, M. Niederst, C. Benes, Jeff Engelman","doi":"10.1158/1557-3265.aacriaslc18-b25","DOIUrl":"https://doi.org/10.1158/1557-3265.aacriaslc18-b25","url":null,"abstract":"","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":"81456425","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 B27: Osimertinib (AZD9291) is sensitive and bound with affinity to EGFR exon 20 insertion mutant models","authors":"Yusoo Lee, T. Kim, Dong-Wan Kim, Y. Ahn, So Yeon Kim, B. Keam, Miso Kim, D. Heo","doi":"10.1158/1557-3265.AACRIASLC18-B27","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-B27","url":null,"abstract":"Background: Although EGFR exon 20 insertion mutation is the third most common among EGFR-mutant NSCLC, this mutation has not been well studied and the first-generation EGFR TKIs are ineffective. In addition, the efficacy of the third-generation EGFR TKIs is controversial. Methods: Various EGFR exon 20 insertion mutation models were developed using Ba/F3 system as follows: C-helix (n=1, A763_Y764insFQEA) and loop following C-helix (n=7). In addition, SNU-3173 cell line was derived from NSCLC patient with EGFR exon 20 insertion mutation. Cell viability assays were performed using EGFR TKIs (gefitinib, erlotinib, dacomitinib, afatinib, rociletinib, olmutinib, nazartinib, and osimertinib). Immunoblotting was performed to evaluate the downstream signals of EGFR pathway. Additionally, the docking homology models of EGFR exon 20 insertion mutations with osimertinib were developed with SWISS-Model and SwissDock for estimation of the structural appropriateness. Results: Cell viability assay showed that EGFR exon 20 insertion mutants are resistant to the first-generation EGFR TKIs, except for A763_Y764insFQEA mutant Ba/F3 cells. IC50 values of second-generation EGFR TKIs are five- to hundreds-folds lower than gefitinib and erlotinib. Dacomitinib and afatinib have good efficacy for the most of them, and regulated down signaling pathways. The third-generation TKIs showed moderate efficacy against EGFR exon 20 insertion mutants. Overall, osimertinib has the most successful inhibition of EGFR exon 20 insertion mutants (IC50 values for C-helix and loop following C-helix mutants for afatinib, Conclusions: Osimertinib showed an outstanding effectiveness against various EGFR exon 20 insertion mutations. In addition, docking simulation of in silico homology models corresponded with the in vitro results. Consequently, osimertinib is effective against EGFR exon 20 insertion mutant models. Citation Format: Yusoo Lee, Tae Min Kim, Dong-Wan Kim, Yong-Oon Ahn, Soyeon Kim, Bhumsuk Keam, Miso Kim, Dae Seog Heo. Osimertinib (AZD9291) is sensitive and bound with affinity to EGFR exon 20 insertion mutant models [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 B27.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84430534","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 B03: Suppression of lung adenocarcinoma growth and metastasis by stromal Hedgehog pathway activation","authors":"S. Kasiri, Baozhi Chen, A. Wilson, A. Reczek, U. Marriam, Z. Zeng, L. Girard, James Kim","doi":"10.1158/1557-3265.AACRIASLC18-B03","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-B03","url":null,"abstract":"Aberrant activation of the Hedgehog (Hh) signaling pathway drives the tumor growth of Gorlin-type cancers, but its role in other epithelial cancers, including non-small cell lung cancer (NSCLC), has been controversial. We used human lung adenocarcinoma (LAD) cell lines and autochthonous lung adenocarcinoma mouse models to elucidate the pathway’s role in lung cancer pathology. SHH and IHH is expressed heterogeneously among >35 tested LAD cell lines, although mostly in mutant Kras cells. SHH secreted from lung cancer cells activated the pathway in co-cultured fibroblasts in a paracrine, rather than autocrine, manner. Treatment with KAAD-cyclopamine, an Hh pathway antagonist, inhibited the growth of high SHH-expressing tumor cells when co-cultured with NIH-3T3 embryonic fibroblasts but not tumor cells alone, further reinforcing the paracrine nature of Hh pathway activation. However, the growth effect due to fibroblast pathway inhibition was diminished when co-cultured with normal lung fibroblasts. Analysis of potential Hh pathway target genes suggest that normal lung fibroblasts secrete ligands that induce a differentiation program in epithelial cells rather than ligands that induce mitogenic programs from NIH-3T3 fibroblasts. In Kras LSL-G12D/+ ;Trp53 fl/fl ; Shh fl/fl \u0000\u0000(KPS) mice, genetic loss of SHH, surprisingly, had no effect on survival compared to Kras LSL-G12D/+ ;Trp53 fl/fl ;Shh +/+ (KP) mice. However, treatment with 5E1, an anti-SHH/IHH blocking antibody, 2 weeks after tumor induction in KP mice resulted in significantly worse survival with increased metastases compared to KP mice treated with control IgG 1 antibody. Furthermore, stromal Hh pathway abrogation by 5E1 led to increased tumor burden and decreased tumor vessel density compared to control mice. To account for the survival differences seen between KP mice with genetic SHH loss and those treated with 5E1, we analyzed KP tumors and found unexpectedly high levels of Ihh mRNA, compared to Shh mRNA, that have not been reported previously in normal or neoplastic murine lungs. Preliminary results using an in vivo CRISPR/Cas9 (pSECC) system to genetically ablate Ihh in Kras LSL-G12D/+ ;Trp53 fl/fl ;Rosa26 LSL-fluc/+ mice showed significant enhancement of tumor growth compared to control mice treated with sgGFP. These results suggest that IHH, rather than SHH, activates a tumor-suppressive program in lung stroma. These results correlate to human survival data of LAD with low lhh mRNA expression (KMPLotter). We are in the process of isolating and examining murine stromal cells from KP mice to identify the secreted stromal factors that limit tumor growth and metastases. Thus, stromal Hh pathway activation, in response to IHH secreted from lung cancer epithelia, suppresses LAD growth and metastases, increases tumor vessel growth, and prolongs survival. Citation Format: Sahba Kasiri, Baozhi Chen, Alexandra Wilson, Annika Reczek, Ummay Marriam, Zhiqun Zeng, Luc Girard, James Kim. Suppression ","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89335023","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 B67: Regulation of a novel cell surface protein in macrophage activity in tumor microenvironment","authors":"Rashmi Ray, V. Rai","doi":"10.1158/2326-6074.TUMIMM17-B67","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B67","url":null,"abstract":"Inflammatory cells and their mediators are an essential component of the tumor microenvironment. Tumor associated macrophages (TAMs) represent a predominant population of inflammatory cells present in the solid tumor and tumor microenvironment. TAMs are associated with tumor progression and metastasis and the infiltration of TAMs or the enrichment of TAM-associated genes relates to poor prognosis and disease outcome in most human tumor types. However, the stimulus and triggers for the tumor cells-macrophage interaction remain unclear. Autotaxin, an ectoenzyme generates smallest phospholipid, lyophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Autotaxin is also known to play important roles in breast cancer, ovarian cancer and many other cancers. LPA is involved in numerous biological processes encompassing cell growth, cell proliferation, cell migration, cancer and metastasis. LPA exerts its functions on different cell types via its different G-protein coupled receptors (GPCRs). More progress has been made in recent years in dissecting the mechanisms of LPA generation and how it directly acts on its target cells. Recently we have shown that LPA converts monocytes into macrophages both in mice and humans. Here, we show that cancer cells in tumor growth are associated with tumor associated macrophages via a signature paracrine link. Our studies identify an unknown signaling link between tumor cells and macrophages. Furthermore, we have functionally characterized these macrophages and the suppression of this paracrine network leads to decrease in tumor growth and its progression. Our preliminary data also shows that blocking of this paracrine link decreases the secretion of proangiogenic factor such as TGF-b, TNF-a, MMP-9, and VEGF. This study suggests that suppression of this paracrine network can act as a new therapeutic approach to control cancer and metastasis. New insights into the role of LPA in regulating immune responses via cancer cells should be explored in the near future. Citation Format: Rashmi Ray, Vivek Rai. Regulation of a novel cell surface protein in macrophage activity in tumor microenvironment [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 B67.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"9 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78643086","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 B43: Novel small-molecule human STING agonists generate robust Type I interferon responses in tumors","authors":"Monali Banerjee, Sandip Middya, Sourav Basu, Ritesh Shrivastava, Rajib Ghosh, Dharmendra B. Yadav, Thanilsana Soram, R. Raina, D. Pryde, Kavita Puniya, Navin Pandit, Rubeenaparveen R. Mansuri, Vijay Kadam, Sabyasachi Debnath, Sunny Goon, A. Singh, Anindita Middya, Nidhi Rawat, A. Surya","doi":"10.1158/2326-6074.TUMIMM17-B43","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B43","url":null,"abstract":"Background: A significant proportion of human cancers grow unchecked by the immune system. These cold or non-inflamed tumors do not have a T cell infiltrate and it has been shown that activation of innate immune signaling through STING (Stimulator of Interferon Genes) generates a Type I interferon (Type 1 IFN) signal that increases T cell infiltration into these tumors leading to significant regression (Woo et al., Ann Rev Immunol 2015). Activation of STING using small molecules is a novel therapeutic approach gaining significant traction in the translational immuno-oncology research community. Methods: We used a pharmacophore based approach to identify small molecule human STING agonists. Our compounds were assessed (1) in reporter gene assays on HEK293T cells containing stably transfected hSTING polymorphs, (2) by immunoblots to confirm pSTING, pTBK1, pIRF3, (3) by real-time PCR monitoring induction of Type I cytokines in human tumor cell lines, isolated human PBMCs and dendritic cells (hDC). Promising lead compounds were further evaluated for anti-tumor activity in c57/BL6 syngeneic and xenografted SCID mice humanized with hPBMC and dendritic cells from human donors. Results: We have designed and synthesized potent non-macrocyclic, non-nucleoside human STING agonists. Our lead compound CRD-100 described here has good oral bioavailability and drug like properties (Patents filed). Treatment of an isolated cell free system containing purified recombinant STING and TBK1 leads to STING phosphorylation confirming that CRD-100 is a direct STING binder. Evidence of direct binding also comes from low temperature isothermal calorimetry. CRD-100 activates all five common hSTING variants with agonist EC50 comparable to CDNs in the pIRF3 reporter assay. Treatment of hSTING transfected cells, human tumors cell lines or hPBMC with CRD-100 leads to phosphorylation of IRF3, TBK1 and STING. CRD-100 also causes the maturation of hDCs and the release of innate and adaptive inflammatory cytokines such as IFNβ and TNFα from hPBMCs. Once fortnightly doses of CRD-100 delivered intra-tumorally caused tumor regression in syngeneic and xenografted tumors. Conclusions: The ability of hSTING agonists to generate anti-tumor immune responses in cold tumors in murine models makes them a promising therapeutic option either as a single agent or in combination with existing or developing therapies. CRD-100 has conventional small molecule drug like properties making it an attractive drug candidate for advanced development as an immune mediated anti-cancer agent. Disclosure of Chemical Structures: We will not be disclosing chemical structures at AACR. Citation Format: Monali Banerjee, Sandip Middya, Sourav Basu, Ritesh Shrivastava, Rajib Ghosh, Dharmendra Yadav, Thanilsana Soram, Ritika Raina, David C. Pryde, Kavita Puniya, Navin Pandit, Rubeenaparveen R. Mansuri, Vijay Kadam, Sabyasachi Debnath, Sunny Goon, Anuj Singh, Anindita Middya, Nidhi Rawat, Arjun Surya. Novel small-molec","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"298 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82866595","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}