Tumor & microenvironment最新文献

{"title":"Abstract B33: Coexpression and frequency of immune checkpoint proteins in the tumor microenvironment analyzed via multiplex immunohistochemistry","authors":"J. Ziello, Sarah R. Klein, K. Crosby","doi":"10.1158/2326-6074.TUMIMM17-B33","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B33","url":null,"abstract":"Antibody blockade of the PD-1/PD-L1 axis is approved for clinical use in multiple tumor types in an effort to block tumor immune evasion. The high number of emerging cancer immunotherapy agents indicates that there is an increased importance in assessing and understanding the immunosuppressive tumor microenvironment. In this study, we applied a 7-color multiplex immunohistochemistry panel to a lung tumor tissue microarray consisting of FFPE adenocarcinoma and squamous cell carcinoma cores. The panel was composed of immune checkpoint receptors PD-1 and TIM-3; PD-L1, a PD-1 ligand; CD68 and CD8, macrophage and cytotoxic T cell markers, respectively; as well as cytokeratin as the tumor mask and DAPI as the nuclear counterstain. The array included three cores per patient, and the concordance between fields was analyzed. Additionally, the frequency and co-localization of these markers and checkpoint proteins in the tumor and tumor microenvironment were quantified. TIM-3 expression was found not only on CD8+ T cells, but also on CD68+ macrophages, where it is thought to have a distinct function involved in phagocytosis of tumor cells. Furthermore, the significant role that macrophages play in tumor progression via promoting angiogenesis and inhibiting antitumor immunity makes these data increasingly relevant. These data demonstrate how antibody-based multiplex analysis in tissue can provide insight into the various cell types involved in tumor-mediated immune evasion. Multiplex IHC with highly specific antibodies will serve to improve our understanding of how immunotherapies can be used to affect the innate and adaptive branches of the immune system in the course of cancer treatment. Citation Format: Jennifer Ziello, Sarah Klein, Katherine Crosby. Coexpression and frequency of immune checkpoint proteins in the tumor microenvironment analyzed via multiplex immunohistochemistry [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 B33.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"113 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79852566","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 B31: A protein synthesis switch underlies initial survival of EGFR-mutant lung cancer to EGFR inhibitors","authors":"Kyung-A Song, Timothy L. Lochmann, Neha U. Patel, Jungoh Ham, Brad Windle, H. Harada, J. Leverson, A. Souers, A. Hata, H. Ebi, A. Faber","doi":"10.1158/1557-3265.AACRIASLC18-B31","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-B31","url":null,"abstract":"EGFR inhibitors (EGFRi) are effective at inducing transient tumor shrinkage in EGFR- mutant lung cancers. The efficacy of these drugs however is mitigated by the outgrowth of resistant cells: this is most often manifested by a secondary mutation in EGFR, T790M , which leads to reactivation of key intracellular signaling despite continued drug treatment. We recently demonstrated that T790M can occur both at low frequencies prior to initiation of EGFR inhibitor therapy, or alternatively arise de novo during treatment (Hata et al., Nat Med 2016). Since some cancers form T790M mutations de novo, one potential therapeutic strategy to thwart resistance is to identify the cells surviving initial therapy (referred to as persister cells or drug-tolerant cells [DTCs]) that eventually acquire the T790M mutation, and eliminate them prior to T790M acquisition. To this end, we hypothesized that some cells were refractory to EGFR inhibitor-induced apoptosis, surviving initial therapy and forming a reservoir of cells that could then eventually acquire T790M . We demonstrate that Western blots of lysates from EGFR- mutant lung cancers surviving initial therapy to the EGFR inhibitor gefitinib detect quick ( EGFR- mutant lung cancer tumors, and the emergence of DTCs could be largely thwarted by co-incubation with MCL-1 specific inhibitors A-1210477 and S63845. Mechanistically, we report DTCs undergo a “translational switch” that manifests in increased cap-dependent mRNA translation of MCL-1, which corresponds to cellular upregulation of mTOR/eIF4 and downregulation of ribosomal proteins. These data reveal a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors by shifting protein biosynthesis through cap-dependent translation of MCL-1 protein. Moreover, in EGFR- mutant lung cancer, MCL-1 is a key molecule governing the emergence of early DTCs to EGFR inhibitors and can be effectively co-targeted with clinically-emerging MCL-1 inhibitors, which may delay the acquisition of secondary mutations including T790M mutations, therefore prolonging therapy efficacy. Citation Format: Kyung-A Song, Timothy L. Lochmann, Neha U. Patel, Jungoh Ham, Brad E. Windle, Hisashi Harada, Joel D. Leverson, Andrew J. Souers, Aaron N. Hata, Hiromichi Ebi, Anthony C. Faber. A protein synthesis switch underlies initial survival of EGFR -mutant lung cancer to EGFR inhibitors [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 B31.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82137457","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 B57: Effect of ADAM17 inhibition on the release of IFN-y during natural killer cell-mediated antibody dependent cellular cytotoxicity in cancer","authors":"H. Mishra, Wu Jianming, N. Pore, B. Walcheck","doi":"10.1158/2326-6074.TUMIMM17-B57","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B57","url":null,"abstract":"Introduction: Antibody-dependent cell cytotoxicity (ADCC) by NK cells is a key mechanism in the anti-cancer effects of therapeutic antibodies. CD16a is an IgG Fc receptor (FcRIII) present on the surface of NK cells and plays essential role in recognizing tumor-bound antibodies to initiate ADCC. NK cells are triggered to release cytokines like IFN-y during ADCC which has been reported to have a number of antitumor activities. A disintegrin and metalloproteinase 17 (ADAM17) plays key role in downregulating CD16a in the tumor microenvironment and facilitate tumor induced anergy through the inactivation of cell cytotoxic function. Downregulation of CD16a on NK cells and decreased levels of IFN-y have been reported in ovarian cancer patients. We hypothesize that by blocking the function of ADAM17 we can enhance IFN-y release during ADCC by maintaining higher CD16a levels on the NK cells. To test this hypothesis, we used ADAM17 function blocking antibody MEDI3622 (MedImmune), HER2 receptor positive ovarian (SKOV-3 and MA148) and CD20 receptor positive lymphoblastoid (Raji) cancer cell lines. To further study the role of CD16a in this process we used monoclonal function block anti-CD16 antibody (clone: 3G8) and cleavage resistant CD16a NK92 cells (CD16a/S197P) where we substituted serine with proline at the location of 197 in the membrane proximal region. Description: NK cells derived from peripheral blood (PBNK) were isolated through negative selection EasySepTM (StemCell, Cat: 19055). These PBNK cells were incubated with target cells in the presence of a therapeutic antibody to initiate ADCC with or without blocking ADAM17 by MEDI3622. The samples were incubated at 37°C in CO2 incubator and the supernatant were collected after 4 hrs of incubation by briefly spinning them at 1500 rpm for 5 minutes. IFN-y was measured through CBA (BD Bioscience, Cat: 560111). Summary: The blocking of ADAM17 by MEDI3622 in the presence of herceptin showed an increase in the IFN-y release in comparison to herceptin alone group during ADCC with two ovarian cancer cell lines i.e. SKOV-3 (p Next we investigated the role of CD16a receptor in the release of IFN-y. We blocked the CD16a receptor with a monoclonal antibody (clone: 3G8) during herceptin mediated ADCC by PBNK cells in SKOV-3 cancer cell line with or without MEDI3622 and found a substantial decrease in the IFN-y release (P In another experiment, where we expressed a cleavage resistant CD16a (CD16a/S197P) in human NK cells line (NK92), we compared the IFN-y release by CD16a/S197P to CD16a/WT NK92 cells during herceptin mediated ADCC in SKOV-3 tumor. In this experiment, NK92a/S197P showed higher release of IFN-y in comparison to NK92aWT (p Conclusion: Our results indicate that the inhibition of ADAM17 enhances the IFN-y release by NK cells during ADCC by blocking the shedding of CD16a. Based on these results, ADAM17 may be considered a checkpoint target to improve tumor killing and its utility can be exploited in canc","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88192600","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 B37: Clinical relevance of tumor-infiltrating immune cells in neuroblastoma","authors":"O. Melaiu, R. Boldrini, M. Chierici, Cesare Furlanello, D. Fruci","doi":"10.1158/2326-6074.TUMIMM17-B37","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B37","url":null,"abstract":"The presence of tumor-infiltrating T cells is crucial for the development of immunotherapies and the prediction of clinical response for many human cancers. Recently, we have shown that tumor-infiltrating T cells have a prognostic value greater than, and independent of, the criteria currently used to stage neuroblastoma, the most common pediatric extra-cranial solid tumor accounting for 15% of childhood cancer-related death. We demonstrated that expression of PD-L1 in tumor cells is inversely correlated with that of HLA class I, and that when combined they represent a promising prognostic biomarker in neuroblastoma. To further dissect the immune heterogeneity of neuroblastoma microenviroment, we evaluated the density of infiltrating dendritic cells (iDC), which are crucial for drug-induced anticancer immune response, in the same cohort of NB samples characterized for type, density, and composition of tumor T lymphocytes and expression of tumor PD-L1 and HLA class I. As for T cells, high density of iDCs was correlated with the presence of infiltrating T cells, expression of tumor HLA class I and favorable clinical outcome, suggesting that iDCs may be critical for robust tumor control by improving prediction of patient survival. Citation Format: Ombretta Melaiu, Renata Boldrini, Marco Chierici, Cesare Furlanello, Doriana Fruci. Clinical relevance of tumor-infiltrating immune cells in neuroblastoma [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 B37.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85384621","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 B15: Increased presence of T follicular helper cells in lung adenocarcinoma is associated with mutational load","authors":"Katey S. S. Enfield, K. Ng, E. Marshall, Spencer D. Martin, W. Lam","doi":"10.1158/1557-3265.AACRIASLC18-B15","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-B15","url":null,"abstract":"Tertiary lymphoid organs are ectopic lymphoid formations found in inflamed tissues such as tumors, and their presence has been associated with improved patient outcome. T follicular helper cells (Tfh) reside in the germinal centre of tertiary lymphoid organs, and are required for the maturation of B cells and subsequent antibody response. Whereas the prognostic value of Tfh has been described in breast and colon tumors, they remain uncharacterized in lung tumors. We hypothesize that Tfh cells reside in lung adenocarcinomas and are associated with an increased immune response due to neoantigen exposure. Gene expression profiles were obtained from 83 paired lung adenocarcinomas and nonmalignant lung tissues from the BC Cancer Agency, and 571 unpaired samples from The Cancer Genome Atlas. Relative proportions of 22 immune cell subsets were inferred from gene expression data using CIBERSORT, a deconvolution algorithm. Identification of tertiary lymphoid organs was achieved through multicolor immunohistochemistry (IHC) staining for T- and B-cell lineage markers (CD3 and CD79a) using whole tissue sections. Proportions of Tfh cells were correlated with tumor mutation load defined as non-silent mutations per megabase (Mann Whitney U test) and patient outcome (Cox proportional hazard model). The proportion of Tfh cells was significantly increased in tumor tissue compared to nonmalignant lung in both cohorts. We also observed concomitant upregulation of Tfh markers PD1 and CXCR5 . Multicolor IHC validated the presence of tertiary lymphoid organs in 19 out of 20 cases assessed. Intriguingly, the increase in the proportion of Tfh cells revealed by CIBERSORT was observed across all disease stages and was validated in an additional cohort of Stage I lung adenocarcinomas. The relative proportion of Tfh cells did, however, increase with increasing tumor mutation burden, suggesting their involvement in an active immune response against tumor neoantigens. Tfh recruitment appears to be an early event in lung tumor progression and a function of neoantigen exposure, suggesting involvement in an active antitumor response rather than a passive result of chronic inflammation. Further investigation into Tfh in lung adenocarcinomas may lead to prognostic applications. Citation Format: Katey S.S. Enfield, Kevin W. Ng, Erin A. Marshall, Spencer D. Martin, Wan L. Lam. Increased presence of T follicular helper cells in lung adenocarcinoma is associated with mutational load [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 B15.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90262808","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 B41: Neutrophils modulate T-cell recruitment and promote hepatic metastases in lung cancer","authors":"R. Rayes, Alexandra Tinfow, Dorothy Antonatos, B. Giannias, J. Spicer","doi":"10.1158/2326-6074.TUMIMM17-B41","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B41","url":null,"abstract":"Immunotherapy using checkpoint inhibitors has shown success in the treatment of late-stage non-small cell lung carcinomas (NSCLC). Indeed, nivolumab (anti-PD1 antibody) increased overall response by 9 % and overall survival by 3 months compared to chemotherapy (docetaxel). Combining Ipilimumab (anti-CTLA-4 antibody), another immune checkpoint inhibitor, with nivolumab was shown to improve response rates and survivals in NSCLC patients compared to nivolumab alone (phase 1/2 study). Despite these advances, there are still many patients that are non-responsive to available immunotherapies. We hypothesize that the immune system can overtake the inhibition of immune suppression via other mechanisms leading to a more immune suppressive tumor microenvironment. Neutrophils, being amongst the first cells of our innate immune system to be recruited to the tumor microenvironment, are key players in modulating other immune cells. Indeed, we and others have demonstrated that neutrophils play a critical role during cancer progression and from a clinical standpoint elevated neutrophil counts both in circulation and within growing lesions have been associated with poor oncologic outcomes. Therefore, neutrophil could well be the immunosuppressive switch in the tumor microenvironment. To test our hypothesis, we injected liver metastatic lung carcinoma cells into mice treated with daily injection of neutrophil elastase inhibitor (NEi, Sivelestat) and into untreated (control) mice. We then collected the livers of those mice at multiple time points post-tumor inoculation and analyzed the immune profile of these mice. As expected, NEi-treated mice had significantly less liver metastases than control mice (p Citation Format: Roni F. Rayes, Alexandra Tinfow, Dorothy Antonatos, France Bourdeau, Betty Giannias, Jonathan D. Spicer. Neutrophils modulate T-cell recruitment and promote hepatic metastases in lung 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 B41.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88972482","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 B42: MDSCs accumulation within metastatic liver is modulated by CXCR4/CXCL12 axis after HSCs interaction with C26 in the ICAM-1 regulated inflammatory milieu","authors":"Aitor Benedicto, Irene Romayor, B. Arteta","doi":"10.1158/2326-6074.TUMIMM17-B42","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B42","url":null,"abstract":"Introduction: Inflammation and immune suppression mediate tumor progression. During liver metastasis, tumor cells interact with and cross the hepatic sinusoidal line formed by liver sinusoidal endothelial cells (LSECs). In this inflammatory milieu, hepatic stellate cells (HSCs) are recruited into the nascent foci initiating the contact with the tumor cells. These cross-talks modulate the tumor microenvironment into a more tolerant one, in part by attracting myeloid derived suppressor cells (MDSCs). However, the mechanisms regulating the initiation of the inflammatory response and the recruitment of HSCs and MDSCs during the development of liver metastasis from colorectal cancer is not fully characterized. We aim to unmask mediators of the inflammatory response triggered after tumor cells interaction with LSECs and in the recruitment of HSC. Besides, the involvement of CXCR4/CXCL12 axis in the cross-talk between tumor cells and the recruited HSCs will be analyzed, with focus on the HSCs-mediated recruitment of MDSCs. Methods: To do so, the involvement of primary LSECs and tumor cells in the levels of inflammatory factors were measured by ELISA. Afterwards, the effect of both tumor-activated LSECs and sICAM-1 activated C26 cells in the recruitment of HSCs and their secretion of promigratory factors was studied. Moreover, the expression and role of CXCR4/CXCL12 axis in amplifying the migratory potential of HSCs and C26 was determined by using CXCL12 and the CXCR4 antagonist AMD3100. Finally, the role of CXCL12-CXCR4 in the hepatic stellate cell and MDSCs recruitment during liver metastasis and disease progression was analyzed in vivo by means of AMD3100 treatment. Results: Tumor-endothelial interplay increased secretion of IL-1β, IL-6, PGE2, and TNF-α, partly abrogated by blocking endothelial ICAM-1. Additionally, sICAM-1 activation of C26 could mimic this inflammatory response. Moreover, sICAM-1 stimulated CT26 derived medium significantly increased not only HSCs migration but also the matrix remodeling factors such as MMP-2 and uPA activity and the angiogenic factor VEGF. Additionally, tumor-derived conditioned medium promoted the expression of CXCR4, while CXCL12 increased the migratory potential of HSCs which was abrogated by blocking CXCL12/CXCR4 interaction through AMD3100. In vivo, the administration of AMD3100 revealed impaired infiltration of ASMA expressing HSCs into the metastatic lesions, along with reduced CD11b+Ly6G+ MDSC counts in the invaded organ. These observations were in line with 2-fold reduced metastatic area in AMD3100 treated mice liver. Conclusions: We can conclude that ICAM-1 mediates the early inflammatory response driving to HSC recruitment and their contribution to matrix remodeling and angiogenesis. These recruited HSC increase their expression of CXCR4 which could amplify their response to CXCL12 and thus trigger a positive feedback recruiting more C26 and HSCs. In vivo, these recruited HSCs might induce the recruitmen","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81043118","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 PR05: Preventing the recurrence of breast cancer at the metastatic niche using resolution-phase macrophages","authors":"Odelya Gilon, Y. Feuermann, Sagie Schif-Zuck, Keren Weidenfeld, P. V. Huth, E. Sabo, A. Ariel, D. Barkan","doi":"10.1158/2326-6074.TUMIMM17-PR05","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-PR05","url":null,"abstract":"Breast cancer that recurs as metastatic disease many years after primary tumor resection and adjuvant therapy appears to arise from tumor cells that disseminated early in the course of the disease but did not develop into clinically apparent lesions. These long-term surviving, quiescent disseminated dormant tumor cells (QDTC) are resistant to conventional therapies that target actively dividing cells. The mechanisms responsible for maintaining the survival and outgrowth of QDTC remain largely unknown. Recently, we found that fibrotic-like microenvironment with extensive deposition of Type I collagen (Col-I) and fibroectin, established at the site of the residing QDTC, promoted the outbreak of QDTC. Therefore, we hypothesized that promoting resolution—the endogenous mechanism that terminates inflammation and fibrotic responses and actively directs tissue return to homeostasis—at the permissive site will “normalize” it and prevent metastatic outbreak. Here we demonstrate that soluble factors secreted by ex vivo generated pro-resolving CD11blow macrophages can inhibit the establishment of a fibrotic niche resulting in the inhibition of the metastatic outgrowth of QDTC. The inhibition of the fibrotic niche was due to inhibition of TGFβ1-induced differentiation of fibroblasts to myofibroblasts and myofibroblasts’ apoptosis. Interestingly, our data also demonstrate that the blockade of fibroblast differentiation to myofibroblasts is not mediated by inhibition of the canonical signaling of TGFβ1. Taken together our results demonstrate a pioneering conceptual approach to “normalize” the microenvironment that supports the outgrowth of QDTC by promoting the tissue resolution axis. This abstract is also being presented as Poster B36. Citation Format: Odelya Gilon, Yonatan David Feuermann, Sagie Schif-Zuck, Keren Weidenfeld, Palle Von Huth, Edmond Sabo, Amiram Ariel, Dalit Barkan. Preventing the recurrence of breast cancer at the metastatic niche using resolution-phase macrophages [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 PR05.","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":"82325692","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 B64: Characterizing the tumor immune microenvironment of metastatic and nonmetastatic renal clear cell carcinomas and colorectal carcinomas using computational methods","authors":"Yasmin Kamal, F. Varn, Chao Chen, H. R. Frost, C. Amos","doi":"10.1158/2326-6074.TUMIMM17-B64","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B64","url":null,"abstract":"Cancer is a leading cause of mortality worldwide with most cancer-related deaths attributed to metastatic disease progression. Engaging the immune system to fight cancer has several advantageous features, particularly given the unique role the immune system plays in initiating, maintaining, and fighting tumor metastasis. Here, we examine the tumor immune microenvironment in metastatic (primary stage IV -M1) and non-metastatic (primary stage I/II- M0) tumors in renal clear cell carcinoma (RCCC) and colorectal carcinoma (CRC) through the application of deconvolution algorithms and pathway analyses. Preliminary data suggests the tumor microenvironment varies based on cancer type as well as metastatic disease status, and these differences in immune infiltration significantly affect survival outcomes. The prevailing belief of the association of CD8+ T cells with a positive survival outcome did not hold true for renal clear cell carcinoma in our analysis. We further characterized the heterogeneity of the microenvironments in CRC and RCCC. Specific immune cell types consistently and differentially infiltrate tumors (NK and CD4+ T cells in particular), albeit their cellular status and influences on survival vastly differ based on the tumor type, suggesting each tumor type uniquely evades the immune system to promote metastasis. Citation Format: Yasmin Kamal, Frederick S. Varn, Jr., Chao Chen, Hildreth Robert Frost, Christopher I. Amos. Characterizing the tumor immune microenvironment of metastatic and nonmetastatic renal clear cell carcinomas and colorectal carcinomas using computational methods [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 B64.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85332164","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 B75: Loss of cross-presentation by tissue resident DC1 in lung adenocarcinomas is an early event that correlates to exhaustion of endogenous antitumor CD8+ T cell responses","authors":"N. Caronni, F. Simoncello, K. Cervantes-Luevano, Licio Collavin, F. Benvenuti","doi":"10.1158/2326-6074.TUMIMM17-B75","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B75","url":null,"abstract":"Recent studies highlighted the essential role of tissue-resident dendritic cells (DCs) for T cells priming and immune checkpoint therapy, however the mechanism leading to DCs suppression during tumor growth are still poorly understood. Here we have isolated CD103 (DC1) and Cd11b (DC2) from orthotopic Kras/Trp53 adenocarcinomas to study their function and gene expression profiles. At early stages of tumor progression (day 14-21) DC1 effectively cross-presented tumor antigens acquired in vivo and this was paralleled by the presence of IFN-γ; secreting tumor specific CD8 + T cells in the lung. Starting from day 28 post tumor inoculation, despite minor changes in tumor burden, DC1 were no longer able to cross present tumor associated antigens and CD8 + T cell responses were concomitantly shut-off. DC1 isolated from tumor bearing lungs and fed with antigen ex-vivo confirmed a selective loss in cross-presentation. In parallel, DC2 skewed their cytokine profile and acquired a Th17 promoting phenotype mediated by high production of IL-23. In order to identify factors causing the sudden loss in DC1 activity we analyzed gene expression profiles in total lung tissues. At day 21 we observed a peak in T cell attracting chemokines together with expression of inhibitory pathways. This signature was dramatically modified at day 28, with a decrease in T cell associated genes and an increase in neutrophils related transcripts. Gene expression profiles in de-activated DC1 showed modulation of transcripts related to innate activation and antigen processing. In summary, this study identifies a narrow temporal window during which tissue resident DCs lose the ability to cross-present tumor associated antigens. Loss of DC1 function is accompanied by cell-intrinsic changes in gene expression, cell extrinsic changes in the tumor microenvironment and loss of activity in endogenous CD8+ T antitumor responses. Citation Format: Nicoletta Caronni, Francesca Simoncello, Karla Cervantes-Luevano, Licio Collavin, Federica Benvenuti. Loss of cross-presentation by tissue resident DC1 in lung adenocarcinomas is an early event that correlates to exhaustion of endogenous antitumor CD8+ T cell 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 B75.","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":"76965184","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}