Tackling the Tumor Microenvironment: Beyond T-cells最新文献

{"title":"The Tumor Microenvironment: Methods and Protocols","authors":"I. P. Witz","doi":"10.1007/978-1-0716-2914-7","DOIUrl":"https://doi.org/10.1007/978-1-0716-2914-7","url":null,"abstract":"","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73714084","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 IA10: PMN-MDSC and neutrophils: Tale of two cells in cancer","authors":"D. Gabrilovich","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-IA10","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-IA10","url":null,"abstract":"Myeloid cells are a critical component of the tumor microenvironment. In cancer, the myeloid compartment is dramatically affected, which is now considered as one of the major immunological hallmarks of cancer. Accumulation of immunosuppressive macrophages (MΦ), defective dendritic cells (DC) function and expansion of pathologically activated immune suppressive immature myeloid cells – myeloid-derived suppressor cells (MDSC) are major changes in the myeloid compartment in cancer. The total population of MDSC consists of three groups of cells: the most abundant (>75%) immature, pathologically activated neutrophils (PMN-MDSC); the less abundant population of pathologically activated monocytes – (M-MDSC). Tumor associated macrophages (TAM) and DCs can persist in tissues for a long time, whereas PMN-MDSC have short lifespan ( Citation Format: Dmitry I. Gabrilovich. PMN-MDSC and neutrophils: Tale of two cells in cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA10.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74680588","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 A102: Rescue of lost skin dendritic cells in melanoma is key for the resuscitation of antitumor T-cell responses","authors":"Anastasia Prokopi, Christoph H Tripp, B. Tummers, Kerstin Komenda, K. Hutter, G. Cappellano, L. Bellmann, M. Efremova, Z. Trajanoski, Suzie Chen, B. Clausen, D. Green, P. Stoitzner","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A102","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A102","url":null,"abstract":"One major characteristic of skin-related cancers is the loss of skin-resident dendritic cell populations. In the tg(Grm1)EPv mouse model, ectopic expression of the metabotropic glutamate receptor-1 in melanocytes leads to a highly proliferative and antiapoptotic phenotype, resulting in melanoma formation within the dermis. The slow progression of these tumors allows for the in depth analysis of the immune infiltrate in growing tumors. We here show that total DCs (CD11c+ cells) are gradually lost as the tumor progresses. Mainly the dermal CD11b+ DCs are affected, whereas epidermal Langerhans cells remain unchanged. We hypothesized that extrinsic cell death of the DCs may be induced within the growing tumor. Indeed, the tumor tissue upregulated the expression of Fas ligand (FasL) that can induce extrinsic apoptosis in immature DCs that express Fas (CD95). Fas-mediated apoptosis depends on the activation of caspase-8 and mice in which the autoproteolytic cleavage site D387 is mutated to alanine (casp8D387A/casp8D387A) show strong resistance to Fas-mediated death. We compared the apoptosis induction in the different DC subsets in casp8WT/casp8WT and in casp8D387A/casp8D387A upon intradermal administration of an agonistic anti-CD95 antibody and we found that, indeed, CD11b+ DCs in WT mice are susceptible to apoptosis via CD95. In order to retrieve the intratumoral DCs, we treated tg(Grm1)EPv mice carrying tumor lesions with Flt3L and the percentages of the CD11b+ subset could be restored back to the levels of tumor-free mice. At the same time, T-cells from both the tumor and the tumor-draining lymph node were able to produce more cytotoxic cytokines. Our data thus indicate that the loss of DCs in melanoma depends on induction of apoptosis within the tumor; rescue of skin DCs may be a promising strategy in order to enhance the efficacy of existing immunotherapeutic strategies against skin-related cancers. Citation Format: Anastasia Prokopi, Christoph H. Tripp, Bart Tummers, Kerstin Komenda, Katharina Hutter, Giuseppe Cappellano, Lydia Bellmann, Mirjana Efremova, Zlatko Trajanoski, Suzie Chen, Bjorn E. Clausen, Douglas R. Green, Patrizia Stoitzner. Rescue of lost skin dendritic cells in melanoma is key for the resuscitation of antitumor T-cell responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A102.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82049989","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 A117: Tumor-produced IL-6 and IL-8 are associated with MDSC accumulation and correlate with long-term clinical outcomes in melanoma patients","authors":"R. Tobin, Kimberly R. Jordan, Dana M Davis, Victoria M. Vorwald, K. Couts, D. Gao, Derek E. Smith, W. Robinson, V. Borges, M. McCarter","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A117","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A117","url":null,"abstract":"Background: Recruitment and expansion of immunosuppressive myeloid cells present a significant barrier to the successful treatment of melanoma. We aimed to identify tumor-secreted factors that altered the frequency of MDSCs and correlated with clinical outcomes in advanced melanoma patients. We hypothesized that production of IL-6 and IL-8 by melanoma tumors would lead to expansion and accumulation of MDSCs and correlate with long-term clinical outcomes. Methods: Expression of IL-6 and IL-8 in melanoma tumors as well as the plasma concentration of IL-6 and IL-8 were measured and compared with the frequency of circulating MDSCs in a total of 52 stage IV melanoma patients. These measures were correlated with tumor burden, BRAF status, lactic acid dehydrogenase (LDH) levels and with clinical outcomes. Samples were collected beginning in January 2011 and clinical follow-up was collected through January 2018. Results: The plasma concentration of both IL-6 and IL-8 correlated with tumor burden (p Citation Format: Richard P. Tobin, Kimberly R. Jordan, Dana Davis, Victoria M. Vorwald, Kasey Couts, Dexiang Gao, Derek E Smith, William A Robinson, Virginia Borges, Martin D McCarter. Tumor-produced IL-6 and IL-8 are associated with MDSC accumulation and correlate with long-term clinical outcomes in melanoma patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A117.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82211454","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 A049: Three-dimensional microfluidic platform mimicking the tumor microenvironment","authors":"A. Pavesi, S. Wong, R. Kamm, S. Lee, Giulia Adriani","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A049","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A049","url":null,"abstract":"Immunotherapy is currently a main breakthrough in cancer treatment, but therapeutic approaches for solid tumors still present limitations in the clinical scenario due to the challenges posed by the immunosuppressive tumor microenvironment (TME). Specifically, among immune cells recruited to the TME, monocytes/macrophages are especially abundant. Macrophages in vitro have been classified as classically activated M1 macrophages and alternatively activated M2 macrophages. However, macrophages are highly plastic cells and they often present mixed phenotypes in the in vivo TME. Monocytes/macrophages are involved in cancer cell proliferation, cell invasion, cell killing, vascular angiogenesis, T-cell immunosuppression, and are often correlated with a poor outcome in an extended range of cancers. However, disrupting the protumor activity of monocytes/macrophages and their interactions with the complex cellular system in the TME remains a challenge. Thus, a better understanding of the mechanisms that modulate monocyte/macrophage phenotype and their interactions with tumors may lead to make them a relevant therapeutic strategy. To study the immunosuppressive TME, we developed microfluidic-based integrated platforms with a 3-dimensional (3D) co-culture of tumor cells and immune cells to investigate how physical and molecular cues in the TME regulate the cellular interplay. Our 3D multicellular platforms offer considerable benefits and have already demonstrated in previous studies a clear advantage over classical 2D platforms to model the TME and to screen for different therapeutic approaches. Our previous studies demonstrated the crucial role of immune system interactions with cancer cells in metastasis either at a primary tumor site or at a secondary metastatic site. Further, we investigated the impact of monocytes and Programmed Death Ligand 1 (PD-L1) immune checkpoint on T-cell receptor (TCR)-engineered T-cells. We have now developed a new 3D microfluidic platform to study the effects of interstitial flow (IF), the flow of fluid through tumor stroma, which is an important component of the TME that may contribute to the polarization of macrophages toward a protumor phenotype. The microfluidic model allows the co-culture of tumor cells and monocytes/macrophages, to stimulate them with IF and to quantify cell migration in 3D. To the best of our knowledge, this study represents the first microfluidic tumor model that incorporates IF and both tumor and immune cells. Our preliminary results confirmed that the presence of tumor cells and hence tumor-cell secreted factors (TSF) increased the migration speed and directedness of macrophages toward cancer cells, potentially contributing to cancer cell dissemination. Interestingly, the presence of the IF-based mechanical cue (without tumor cells in culture) resulted in a similar increase in macrophage migration. Further, by combining both TSF and IF we observed no synergistic or additive effect on macrophage migrat","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87109731","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 A118: Clinical impact of PD-L1 expression and epithelial-mesenchymal transition in the tumor microenvironment of extrahepatic cholangiocarcinoma","authors":"T. Tsuchikawa, T. Ueno, Osamu Sato, Toru Nakamura, Y. Nakanishi, T. Asano, T. Noji, K. Okamura, T. Shichinohe, S. Hirano","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A118","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A118","url":null,"abstract":"Background: Extrahepatic cholangiocarcinoma (eCCA) has a poor prognosis. Although the possibility of immunotherapy has been studied, immune checkpoint molecules such as programmed death ligand 1 (PD-L1) in eCCA are not well understood. Epithelial-mesenchymal transition (EMT) has recently been shown to regulate PD-L1 expression. Our aims were to assess the clinicopathological significance of tumor-infiltrating lymphocytes (TILs) and tumor PD-L1 expression in eCCA and to compare these immune responses with EMT marker expression. Material and Methods: An immunohistochemical evaluation using a TMA method at a single large center was performed. Patients (n = 117) underwent surgical resection in the Department of Gastroenterological Surgery II at Hokkaido University Hospital between January 1995 and November 2006 and eCCA tumors were confirmed histopathologically. We investigated the level of infiltration of immune cells positive for CD4, CD8, Foxp3, PD-L1 in addition to E-cadherin, N-cadherin, Vimentin, ZEB1, ZEB2, SNAIL, TWIST expression, statistically comparing correlations among these factors. Results: High numbers of CD4+ and CD8+ TILs correlated with node-negative (P = 0.009 and P = 0.046, respectively) and low SNAIL expression (P = 0.016 and P = 0.022, respectively). High PD-L1 expression was associated with poor histopathologic classification (P = 0.034), and low E-cadherin (P = 0.001), high N-cadherin (P = 0.044), high vimentin (P Citation Format: Takahiro Tsuchikawa, Takashi Ueno, Osamu Sato, Toru Nakamura, Yoshitsugu Nakanishi, Toshimichi Asano, Takehiro Noji, Keisuke Okamura, Toshiaki Shichinohe, Satoshi Hirano. Clinical impact of PD-L1 expression and epithelial-mesenchymal transition in the tumor microenvironment of extrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A118.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82925411","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 PR15: The oncometabolite R-2-Hydroxyglutarate suppresses the innate immune microenvironment of IDH1-mutated gliomas via aryl hydrocarbon receptor signaling","authors":"M. Friedrich, L. Bunse, T. Bunse, E. Green, T. Kessler, S. Pusch, Katrin Deumelandt, R. Carretero, A. Deimling, F. Quintana, W. Wick, M. Plattén","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-PR15","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-PR15","url":null,"abstract":"Background: IDH1-mutated gliomas are associated with less abundant and phenotypically skewed innate and adaptive immune cell infiltrates compared to IDH1 wild-type tumors. Despite this, the most frequent mutation—IDH1R132H—represents a clonal shared neoantigen and mutations in IDH are associated with a more favorable prognosis. While the tumor cell-intrinsic consequences of the oncometabolite R-2-hydroxyglutarate (R-2-HG) accumulating in IDH1-mutated gliomas as a result of a neomorphic enzymatic function are well-characterized, potential direct paracrine effects of R-2-HG influencing the glioma immune microenvironment remain incompletely understood. Aim: This study aimed at characterizing the impact of the oncometabolite R-2-HG on the innate immune microenvironment of IDH1-mutated gliomas. Methods and Results: By means of comprehensive analyses of expression datasets from human gliomas and syngeneic murine tumor models as well as transporter studies, we demonstrate that R-2-HG is imported by both microglia and macrophages via SLC family transporters and suppresses their function in a paracrine manner. Functional analyses of microglia and macrophages indicate an R-2-HG-driven induction of tolerogenicity as evidenced by accumulation of IL10 and TGFβ and suppression of MHC-II expression, which results in impaired activation of antigen-specific T-cells and activation of immune checkpoint molecules. Multilevel signature profiling of human tumor-infiltrating as well as primary immune cells was complemented by reporter gene assays and pathway analyses and revealed that R-2-HG activates the cytosolic transcription factor aryl hydrocarbon receptor (AHR), a key immunomodulatory target of immunosuppressive tryptophan metabolism. By means of knockout models, the observed immunosuppressive phenotype was shown to be AHR-dependent. Functional relevance of R-2-HG-mediated, AHR-driven impairment of myeloid cell immunity was demonstrated in vivo by pharmacologic AHR inhibition, increasing the efficacy of checkpoint blockade. Conclusion: R-2-HG impairs antitumor immunity in IDH1-mutated gliomas by activating the AHR in innate immune cells, thus suppressing the innate immune microenvironment by compromising antigen presentation and activation of antigen-specific T-cells. This, together with recent findings on inhibitory effects on T-cell immunity, represents a novel mechanism of immune evasion of an immunogenic driver mutation and opens a novel therapeutic approach to IDH1-mutated gliomas. Citation Format: Mirco Friedrich, Lukas Bunse, Theresa Bunse, Edward Green, Tobias Kessler, Stefan Pusch, Katrin Deumelandt, Rafael Carretero, Andreas von Deimling, Francisco J Quintana, Wolfgang Wick, Michael Platten. The oncometabolite R-2-Hydroxyglutarate suppresses the innate immune microenvironment of IDH1-mutated gliomas via aryl hydrocarbon receptor signaling [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translat","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89741420","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 A080: Cytokine-induced senescence in neuroblastoma cell lines: Therapeutic option or idle wish?","authors":"Theresa Harmuth, F. Heubach, T. Wieder, R. Handgretinger, P. Lang","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A080","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A080","url":null,"abstract":"We investigated whether treatment with the T helper cell 1 (TH1) cytokines TNF-α and IFN-γ drives neuroblastoma (NB) cell lines into permanent growth arrest. Introduction: Most cancer immunotherapies focus on cytotoxic treatment strategies mediated by CD8-positive cytotoxic T lymphocyte or NK cell responses. However, besides killing, induction of permanent tumor growth arrest is another important mechanism of cancer control. TNF-α and IFN-γ are known to induce senescence in a large number of human cancers. Thus, we investigated their potential to drive NB cell lines into senescence as well. Methods: We evaluated growth arrest in 7 different NB cell lines (LS, LAN-1, SH-SY5Y, SHEP, SK-N-AS, SK-N-BE(2) and Kelly), and in the TH1 cytokine-sensitive melanoma cell line WM115, which was used as a positive control. Cells were cultivated in medium alone (control group) or in medium supplemented with TNF-α (10 ng/ml) and IFN-γ (100 ng/ml) for 96 hrs (treated group). After treatment, cell cycle was evaluated using a 5-ethynyl-2´-deoxyuridine (EdU) assay. Additionally, we investigated whether or not growth arrest persists upon withdrawal of TNF-α and IFN-γ. For growth arrest assays, cells were first treated as described above (2 passages) and subsequently reseeded without addition of TNF-α and IFN-γ. Results: Cell cycle analysis: 5 out of 7 NB cell lines showed reduced percentage of S-phase cells (S) while the G1/G0 fraction (G) increased. This change was significant (p 1.5 but still ≤ 50% of the PF calculated for the control group. Shown is control vs. treated group. According to this definition cell lines are defined as (A) senescent: LS (2.3 vs. 1), SHEP (13 vs. 0.7), Kelly (6.4 vs. 1.5), WM115 (3.8 vs. 0.7) (B) partial senescent: SH-SY5Y (5.6 vs. 2.4), LAN-1 (7.0 vs. 1.6) (C) not senescent: SK-N-AS (6.1 vs. 3.3), SK-N-BE(2) (9.6 vs. 9.4). Conclusion: TNF-α und IFN-γ mediate inhibition of the cell cycle in the majority of tested NB cell lines as determined by the EdU assay. For 3 cell lines, inhibition of the cell cycle was confirmed in growth assays and shown to be permanent (LS, Kelly and SHEP). This was not true for the other two cell lines SH-SY5Y and SK-N-AS that both restarted proliferation upon withdrawal of TNF-α and IFN-γ. On the other hand, LAN-1 was apparently not affected in the cell cycle assay but drastically slowed down its proliferation rate after repeated TNF-α and IFN-γ treatment in the cell growth assays. SK-N-BE(2) was not affected in any of those experiments. In summary, these results suggest that some of the NB cell lines are able to completely arresT-cell growth upon treatment with TNF-α and IFN-γ while other cell lines are only temporarily or not at all affected. Future experiments will aim to confirm cytokine-induced senescence in NB cell lines by detection of several senescence markers, e.g., senesecence-associated beta-galactosidase or induction of p16Ink4a. Citation Format: Theresa Harmuth, Florian Heubach, Thomas Wieder, Rupe","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90433388","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 A120: Intratumoral dendritic cell dynamics in responsive and nonresponsive syngeneic murine tumor models","authors":"Huizhong Xiong, S. Mittman, Ryan Rodriguez, M. Moskalenko, P. Sanchez, Yagai Yang, R. Cubas","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A120","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A120","url":null,"abstract":"Conventional dendritic cells (cDC) play a vital role in T-cell-mediated antitumor immunity by transporting and cross-presenting tumor antigens to CD8 T-cells in draining lymph nodes (dLN) and tumor tissue. DC maturation and antigen uptake takes place in the tumor, which can be heavily affected by the suppressive tumor microenvironment. Intratumoral DCs are a scarce population and their phenotypes and functions have not been fully understood. Here we thoroughly characterized cDC phenotypes and dynamics in a variety of commonly used syngeneic murine tumor models, both at baseline and following anti-PD-L1 (aPDL1) treatment to investigate the correlation and potential contribution of DCs to response. Surprisingly, we observed a lower density of intratumoral DCs in responsive tumor models when compared to nonresponsive ones and their abundance was further reduced by aPDL1 treatment in an IFNg-dependent manner. Their PDL1 expression levels, albeit lower than tumor macrophages, were positively correlated with response. These results demonstrate an inverse correlation between intratumoral DCs and aPDL1-mediated antitumor immunity across different syngeneic murine tumor models, and ongoing studies are exploring the fates of these intratumoral DCs with a focus on their causal relation with the efficacy of immunotherapy. Citation Format: Huizhong Xiong, Stephanie Mittman, Ryan Rodriguez, Marina Moskalenko, Patricia Pacheco Sanchez, Yagai Yang, Rafael Cubas. Intratumoral dendritic cell dynamics in responsive and nonresponsive syngeneic murine tumor models [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A120.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76645020","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 A081: Tumors expressing ACKR1 exhibit a unique signature of tumor-infiltrating immune cells in women with breast cancer","authors":"Brittany D. Jenkins, T. Fleifel, R. Martini, H. Ali, L. Newman, M. Davis","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A081","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A081","url":null,"abstract":"Tumor-associated immune cells, stroma and several other cell types make up the complex tumor microenvironment (TME) that contributes to a broad spectrum of potential clinical outcomes for breast cancer (BC) patients. Part of this delicate interplay is the interaction between pro-inflammatory chemokines and their receptors, which direct the migration of immune cells to areas of tumor-associated inflammation. Our focus in this complex process is on the role of the Atypical Chemokine Receptor 1 (ACKR1/DARC). In general immune response, its expression on erythrocytes helps to maintain chemokine homeostasis by sequestering chemokines in circulation while its expression on endothelial tissue transcytoses the chemokines from tissue into circulation, which ultimately affects which immune cells are brought to the TME. Its role in epithelial tissue expression is less understood. The purpose of this study is to investigate differential gene expression of ACKR1 in breast epithelial tumor tissue through IHC methods, and to determine how that expression correlates with both circulating and infiltrating proinflammatory chemokines. In addition, we will show this role to be associated with specific classes of tumor-infiltrating lymphocytes (TIL) in BC. Circulating chemokine levels for a variety of ACKR1-associated proinflammatory chemokines were determined using Luminex multiplexing assays. Results from our study cohort indicate differential expression of ACKR1 on epithelial tumor tissue, which correlated with a unique signature of immune cell infiltrates and associated proinflammatory chemokines. Tumors positive for AKCR1 expressed higher levels of circulating and infiltrating CCL2 (MCP-1) and lower levels of CXCL8 (IL-8). Tumor-expressing ACKR1 was also found to be associated with T-cells, B-cells, macrophages, and monocytes, where positive tumors tended to express a more robust profile of TILs. Our preliminary data suggest the presence or absence of ACKR1 on breast epithelial tumor tissue can influence the chemokine and immune cell profile within the TME, which can ultimately influence tumor aggressiveness, proliferation, and response to treatments, such as immunotherapies. Citation Format: Brittany D. Jenkins, Talina Fleifel, Rachel Martini, Haythem Ali, Lisa Newman, Melissa Davis. Tumors expressing ACKR1 exhibit a unique signature of tumor-infiltrating immune cells in women with breast cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A081.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74586835","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}