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

{"title":"Abstract PR10: Reprogramming myeloid cells in TME with pepinemab, first-in-class semaphorin 4D MAb, enhances combination immunotherapy","authors":"E. Evans, H. Bussler, C. Mallow, C. Reilly, Sebold Torno, Maria Scrivens, Alan P. Howell, Leslie Balch, J. Leonard, T. Fisher, C. Allen, Paúl E. Clavijo, Gregory Lesiniski, Christina Wu, S. Hu-Lieskovan, A. Ribas, Emily G Greengard, Ernest S. Smith, M. Zauderer","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-PR10","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-PR10","url":null,"abstract":"Purpose: Tumor growth inhibition by anti-semaphorin 4D (SEMA4D, CD100) blocking antibody is enhanced when combined with various immunotherapies in preclinical animal models. Immune checkpoint combinations with pepinemab (VX15/2503), a humanized anti-SEMA4D antibody, are currently being evaluated in several clinical trials. Methods: Expanded mechanistic studies in syngeneic preclinical models investigated the effect of SEMA4D blockade on immune contexture within the tumor microenvironment, as a single agent and in combination with various immunotherapy agents. Antitumor activity and immune response was characterized by immunohistochemistry, flow cytometry, functional assays, and cytokine, chemokine and gene expression analysis. Pepinemab (VX15/2503) is currently being evaluated as single agent or in combination with other immunotherapies in four clinical trials: (i) a phase 1b/2a combination trial of pepinemab with avelumab in NSCLC (CLASSICAL-Lung) (NCT03268057); (ii) a phase 1 combination trial of pepinemab with nivolumab or ipilimumab in melanoma patients who have progressed on any anti-PD-1/PD-L1 (NCT03373188); (iii) a neoadjuvant integrated biomarker trial in patients with metastatic colorectal and pancreatic cancers treated with pepinemab in combination with nivolumab or ipilimumab (NCT03373188); and (iv) a phase 1/2 trial of pepinemab in children with solid tumors and children and young adults with osteosarcoma (NCT03320330). Results: SEMA4D exerts multifaceted effects within the tumor microenvironment by creating a barrier at the tumor-stroma margin to restrict immune cell infiltration and promoting immunosuppressive activity of myeloid-derived cells. Blocking antibody to SEMA4D directly enhanced M1/M2 ratio and both reduced expression of chemokines that recruit MDSC and the ability of MDSC to suppress T-cell proliferation. Antibody blockade reduced the function of immunosuppressive myeloid and regulatory T-cells in the TME while simultaneously restoring the ability of dendritic cells and cytotoxic T-cells to migrate into the tumor in several syngeneic tumor models. Importantly, anti-SEMA4D MAb enhanced the activity of co-administered immunotherapies in murine colon, head and neck (HNSCC), and melanoma models. For example, anti-SEMA4D plus anti-CTLA-4 resulted in 100% survival and 90% complete tumor rejection (CR) (p Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Alan Howell, Leslie Balch, John E. Leonard, Terrence L. Fisher, Clint Allen, Paul Clavijo, Gregory Lesiniski, Christina Wu, Siwen Hu-Lieskovan, Antoni Ribas, Emily Greengard, Ernest S. Smith, Maurice Zauderer. Reprogramming myeloid cells in TME with pepinemab, first-in-class semaphorin 4D MAb, enhances combination immunotherapy [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. Philadelphi","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74387619","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 A110: Efficacy of anti-PD1 immune checkpoint blockade involves the cooperative interaction of myeloid and lymphoid subpopulations in the tumor microenvironment","authors":"Sjoerd T. T. Schetters, Y. Kooyk","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A110","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A110","url":null,"abstract":"Suppression of the immune system by solid malignancies has proven to be a driving force of tumor development and an effective target for therapeutic intervention. The suppression of cytolytic T-cells by inhibitory receptors like PD1 can be blocked by antagonistic antibodies, reinvigorating suppressed antitumor responses. Nonetheless, only a minority of patients show clinical benefit. It is becoming clear the efficacy of checkpoint blockade relies on many factors, including pretreatment conditions, collaboration between innate and adaptive immune cells and immune-architecture of the tumor microenvironment (TME). To investigate this, we studied the immune profiles of the PD1-unresponsive murine B16 melanoma and PD1-responsive MC38 colorectal carcinoma models, systemically and in the TME before and during treatment. By using high-dimensional flow cytometry and unsupervised clustering analyses based on immune checkpoints, we show comparable early establishment of heterogeneity of tumor-infiltrating CD8+ and CD4+ T-cells. However, PD1-responsive MC38 tumor shows correlations in abundance between specific CD8+ T-cell, NK cells and myeloid subsets before checkpoint blockade treatment, while the PD1-unresponsive B16 tumors do not show lymphoid-myeloid codependences. Interestingly, the abundance of monocyte-derived dendritic cells did not increase upon anti-PD1 treatment but instead showed abundance correlation with PD1 CD4+ and CD8+ T-cells, suggesting a putative interaction. The unresponsive B16 tumors showed increased correlation of cDC1 and cDC2 with Foxp3+ regulatory T-cells. We have visualized these putative interactions within the myeloid and lymphoid population in the changing immune-architecture of the TME, using multiplex fluorescence and confocal microscopy. We show heterogeneity and interactive hotspots during immune checkpoint blockade and postulate that successful anti-PD1 treatment requires the location-dependent cooperation of specific myeloid and lymphoid subsets in the TME. Citation Format: Sjoerd Schetters, Yvette Van Kooyk. Efficacy of anti-PD1 immune checkpoint blockade involves the cooperative interaction of myeloid and lymphoid subpopulations in the tumor microenvironment [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 A110.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90303561","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 A082: Single-cell RNA-sequencing of metastatic melanoma identifies a cancer cell-intrinsic program associated with immune checkpoint inhibitor resistance","authors":"Livnat Jerby, P. Shah, Michael S. Cuoco, Christopher Rodman, Mei-ju Su, Johannes Melms, Rachel Leeson, Abhay Kanodia, Shaolin Mei, Jia-Ren Lin, Shu Wang, Bokang Rabasha, David Liu, Gao Zhang, Claire Margolais, Orr Ashenberg, P. Ott, E. Buchbinder, R. Haq, Stephen F. Hodi, G. Boland, R. Sullivan, Dennie T. Frederick, B. Miao, Tabea Moll, K. Flaherty, M. Herlyn, R. Jenkins, Rohit Thummalapalli, Monika S. Kowalczyk, I. Canadas, B. Schilling, Adam N. Cartwright, Adrienne M. Luoma, Shruti Malu, P. Hwu, C. Bernatchez, M. Forget, D. Barbie, A. Shalek, I. Tirosh, P. Sorger, K. Wucherpfennig, E. Allen, D. Schadendorf, B. Johnson, Asaf Rotem, Orit Rosenblatt-Rozen, L. Garraway, Charles H. Yoon, B. Izar, A. Regev","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A082","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A082","url":null,"abstract":"Immune checkpoint inhibitors (ICI) produce durable responses in some melanoma patients, but many patients derive no clinical benefit. The molecular underpinnings of ICI resistance involve intricate cell-cell interactions that are yet elusive. To systematically map the interactions between malignant and immune cells in the tumor ecosystem, we applied single-cell RNA sequencing to 31 human melanoma tumors, profiling thousands of malignant, immune, and stromal cells. We identified a transcriptional program in malignanT-cells that is strongly associated with T-cell exclusion and immunotherapy resistance. Using highly multiplexed in situ imaging we first demonstrated that this program characterizes malignanT-cells in “cold” niches. Next, we showed that the program predicts clinical responses to ICI according to multiple independent validation cohorts, including a new cohort that we obtained from 112 melanoma patients treated with anti-PD-1 therapy. We then identified CDK4/6 as master regulators of this resistance program, and found that CDK4/6 inhibitors repress the program and shift melanoma cells into a senescence-associated secretory phenotype. Lastly, we showed that CDK4/6-inhibition leads to a substantial reduction in melanoma tumor outgrowth in a B16 mouse model when given in combination with immunotherapy. Taken together, our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and forms a basis for the development of novel therapeutic strategies that could overcome immunotherapy resistance. Citation Format: Livnat Jerby, Parin Shah, Michael S. Cuoco, Christopher Rodman, Mei-Ju Su, Johannes M. Melms, Rachel Leeson, Abhay Kanodia, Shaolin Mei, Jia-Ren Lin, Shu Wang, Bokang Rabasha, David Liu, Gao Zhang, Claire Margolais, Orr Ashenberg, Patrick A. Ott, Elizabeth I. Buchbinder, Riz Haq, Stephen Hodi, Genevieve M. Boland, Ryan J. Sullivan, Dennie Frederick, Benchun Miao, Tabea Moll, Keith Flaherty, Meenhard Herlyn, Russell S. Jenkins, Rohit Thummalapalli, Monika S. Kowalczyk, Israel Canadas, Bastian Schilling, Adam N.R Cartwright, Adrienne M. Luoma, Shruti Malu, Patrick Hwu, Chantale Bernatchez, Marie-Andree Forget, David A. Barbie, Alex K. Shalek, Itay Tirosh, Peter K. Sorger, Kai W. Wucherpfennig, Eliezer M. Van Allen, Dirk Schadendorf, Bruce E. Johnson, Asaf Rotem, Orit Rosenblatt-Rozen, Levi A. Garraway, Charles H. Yoon, Benjamin Izar, Aviv Regev. Single-cell RNA-sequencing of metastatic melanoma identifies a cancer cell-intrinsic program associated with immune checkpoint inhibitor resistance [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 A082.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85331088","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 A096: The potential role of fibroblast activation protein as a natural killer cell immune checkpoint","authors":"Allison O'Connell, Shangzi Wang, L. Weiner","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A096","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A096","url":null,"abstract":"Fibroblast activation protein (FAP) is a type II transmembrane serine protease that functions as both a dipeptidyl peptidase and an endopeptidase. FAP is minimally expressed in normal pancreas but overexpressed in 90% of pancreatic ductal adenocarcinoma (PDAC) specimens. A meta-analysis of PDAC studies demonstrated elevated tumor FAP expression is associated with worse clinical outcomes. While immunotherapy offers remarkable results for certain cancer types, it has been largely ineffective in PDAC. This lack of efficacy may be attributed to the dense stromal fibrosis, comprised largely of pancreatic stellate cells (PSCs), that is characteristic of PDAC lesions. Here we demonstrate that human NK cell line (NK92) is activated by and kill PSCs. Upon direct contact with PSCs, NK92 cells upregulate FAP. FAP expression by NK92 cells is associated with an inactivation phenotype. Talabostat, a non-specific inhibitor of FAP, enhances NK92 killing of PSCs in vitro and enhances PDAC tumor clearance in vivo. This suggests that FAP may be a novel NK cell immune checkpoint that can be pharmacologically modulated to enhance NK cell antitumor activity. Citation Format: Allison O9Connell, Shangzi Wang, Louis M. Weiner. The potential role of fibroblast activation protein as a natural killer cell immune checkpoint [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 A096.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74654476","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 A048: Targeting the tumor microenvironment to enhance immunotherapy against cancer","authors":"C. Slaney, A. Oliver, M. Kershaw","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A048","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A048","url":null,"abstract":"Immunotherapies that harness the immune system against cancer are an attractive proposition for cancer treatment. While there have been some promising successes, only a small fraction of patients obtain clinical benefit. It has become clear that the immunosuppressive tumor microenvironment (TME) is a major obstacle for immunotherapies, because the TME suppresses immune responses, leading to reduced efficacy. We previously demonstrated that the site of tumor growth is a major determinant in sculpting the organ-specific TME, and thus predisposes treatment efficacy (1). In this project, we hypothesize that the TME of visceral tumors is more immunosuppressive than those of the tumors growing elsewhere. We investigated in murine models the difference in the TME in breast cancer growing orthotopically and the same breast cancer growing in the common metastatic sites, such as the lungs. Our findings showed that the breast cancer growing in the lungs was resistant to immunotherapies such as anti-PD1 and anti-CTLA-4, whereas the breast cancer growing orthotopically could be completely eradicated even when the cancer burden was greater. Through an institutional prospective community-based rapid autopsy program (CASCADE), we obtained genetically matched metastases and surrounding tissues from several sites in the same breast cancer patients and investigated the TME from these tumors using novel technologies such as RNAseq and multiplex immunohistochemistry. Strikingly, the TMEs from the same organs in different patients have similar immune gene expression profiles and in contrast, TMEs from the same patient differ greatly in different organs. Together, our research demonstrates an organ-specific difference between TMEs that leads to different responses to therapies. We anticipate that further study of how cancer cells sculpt the TME at different sites will greatly enhance our understanding of the TME and provide promising targets to enhance current immunotherapies, especially for patients who do not respond to existing therapies. Reference: 1. Devaud C., et al. Molecular Therapy 2014;22:18-27. Citation Format: Clare Y. Slaney, Amanda J. Oliver, Michael H. Kershaw. Targeting the tumor microenvironment to enhance immunotherapy against 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 A048.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75701050","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 A103: Allosteric inhibition of SHP2 induces antitumor immunity in PD-1-sensitive tumors through modulation of both innate and adaptive mechanisms","authors":"E. Quintana, Kasia Mordec, R. Nichols, D. Wildes, C. Schulze, D. Myers, Mallika Singh, E. Koltun, A. Gill, S. Kelsey, M. Goldsmith, Jan Smith","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A103","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A103","url":null,"abstract":"The protein-tyrosine phosphatase SHP2, encoded by PTPN11, is a known oncogenic driver in a subset of cancers and a central signaling node in the RTK-RAS-MAPK pathway. Genetic and pharmacologic evidence supports a role for SHP2 in driving the proliferation of cancer cells dependent upon a range of activated RTKs, certain RAS and BRAF mutations, and NF1 loss of function mutations. In contrast, a role for SHP2 in antitumor immunity is not well established. SHP2 binds to phosphorylated ITIM and ITAM domains on regulatory receptors in immune cells and multiple reports have demonstrated a SHP2/PD-1 physical interaction. Recently it has been proposed that SHP2 transduces the PD-1 inhibitory checkpoint signal by direct de-phosphorylation of CD28. In this study we show that a peptide comprising two tyrosine phosphorylated 9-mers sequences from the PD-1 ITAM (connected by a PEG8 linker) can activate purified SHP2 enzyme. We also demonstrate that, like checkpoint inhibitors, allosteric inhibition of SHP2 activates NFAT-mediated gene expression in a reporter gene PD-1/PD-L1 bioassay. Based on these findings, we evaluated the impact of SHP2 inhibition on murine host immune cells and the tumor immune microenvironment in vivo using RMC-4550, a novel small-molecule allosteric inhibitor of SHP2. Oral daily administration of RMC-4550 significantly inhibited tumor growth in three syngeneic tumor models sensitive to checkpoint blockade. The inhibitory activity was comparable, and in some cases superior, to checkpoint inhibition. RMC-4550 did not inhibit growth in any of these cancer cell lines in vitro, suggesting that activity was not due to a tumor cell intrinsic antiproliferative effect. Rather, antitumor activity in vivo reflected modulation of murine host immune cell function. First, RMC-4550 did not inhibit tumor growth in immunocompromised Rag-2-deficient mice. Second, efficacy was significantly attenuated when CD8+T-cells were depleted in immunocompetent mice, suggesting that CD8+T-cells were important for tumor growth inhibition. Third, Shp2 inhibition had additive activity in combination with anti-CTLA4 or anti-PD-L1 treatment, resulting in complete tumor regression in some mice. Rechallenge studies also demonstrated the presence of immunologic memory induced by combination therapy. The additive activity with checkpoint blockade suggests an additional mechanism of action beyond inhibition of the checkpoint signal. Fourth, analysis of the immune landscape in the tumor microenvironment indeed revealed modulation of both adaptive and innate immune mechanisms. Similar to checkpoint blockade, RMC-4550 increased the frequency of CD8+T-cell infiltrates in tumors with a corresponding decrease in their PD-1 expression. In addition, Shp2 inhibition significantly shifted polarized macrophage populations by markedly increasing M1 and decreasing M2, effects not seen with anti-CTLA4 or anti-PD-L1. Collectively, these results suggest that SHP2 inhibition is not identical","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77546912","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 A094: Characterization of pancreatic cancer endothelial cells: Approach to enhance immune cell infiltration for immunotherapy","authors":"K. Nakajima, Y. Ino, T. Iwasaki, N. Hiraoka","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A094","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A094","url":null,"abstract":"The hurdles in realizing immunotherapy success for cure stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. We previously proposed that these phenomena are due, in part, to the deployment of tumor-associated antigens, or employment of tumor-associated endothelium acting as a gatekeeper for immune cell infiltration into the cancer tissue (Nakajima et al, Cancer Res 2017;77:5441-4). Here, an extensive study unveiled functional/molecular differences of endothelium derived from pancreatic cancer and normal pancreas. They were isolated from fresh surgical specimen by magnet-based selection. The primary culture of tumor-associated endothelial cells was confirmed by double positive expressions of endothelial markers, CD31 and ERG1. They showed the short vessel formations and the narrow area of capillary network, indicating the low potential of angiogenesis. Further, peripheral blood–derived lymphocytes were less adhering to the tumor-associated endothelial cells. To find the molecular differences, microarray analysis was performed, and identified 2748 molecules distinct from endothelial cells of noncancerous tissues (p Citation Format: Kosei Nakajima, Yashunori Ino, Toshimitsu Iwasaki, Nobuyoshi Hiraoka. Characterization of pancreatic cancer endothelial cells: Approach to enhance immune cell infiltration for immunotherapy [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 A094.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82085679","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 A106: Higher numbers of cancer stem cells in the peripheral blood of children with B-ALL after chemotherapy","authors":"M. Salem, M. Attia, S. Abdou, Abdel-Aziz A Zidan, Mona F Zidan","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A106","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A106","url":null,"abstract":"Background: Acute lymphocytic leukemia (ALL) is biologically and clinically considered as a heterogeneous neoplasm of lymphoid progenitor cells in the bone marrow (BM). 15- 20 % of children with ALL who achieve an initial remission, will show relapse. One potential mechanism behind this relapse could be the emergence of cancer stem cells (CSCs), which are considered the driving force of tumorigenesis due to their ability of self-renewal as well as the emergence of immune regulatory cells including myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Treg). Aim: The main aim of this study was to analyze the numbers of CSCs and correlate these numbers with the numbers of blasT-cells, MDSCs and Treg cells in children with B-ALL before and after induction of chemotherapy. Materials and Methods: CSCs were defined as CD45dimCD19+CD10+CD34+CD38-, MDSCs were defined as Lin-HLA-DR-CD33+CD11b+ and Treg cells were defined as CD4+CD25+CD127-. The frequencies of these cells were analyzed in the peripheral blood of B-ALL patients before (n= 10) and after (n= 10) induction of chemotherapy using flow cytometry. Results: Significant increases in the numbers of CSCs were shown in B-ALL patients after induction of chemotherapy as compared to newly diagnosed patients (7.6± 8.3 vs. 2.7± 2.4, P Citation Format: Mohamed Labib Salem, Mohamed Attia, Said Abdou, Abdel-Aziz A. Zidan, Mona F. Zidan. Higher numbers of cancer stem cells in the peripheral blood of children with B-ALL after chemotherapy [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 A106.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":"145 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87968135","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 A090: The Duffy Antigen Receptor for Chemokines (DARC) influences levels of tumor-associated leukocytes in the breast tumor microenvironment","authors":"Rachel N. Martini, Brittany D. Jenkins, C. Yates, L. Newman, M. Davis","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A090","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A090","url":null,"abstract":"The regulation of immune cell infiltration into the tumor microenvironment can influence disease prognosis. The specific populations that are present can inform potential treatment options. This work investigates immune cell regulation in the breast cancer tumor microenvironment, specifically how an atypical chemokine receptor, known as the Duffy Antigen Receptor for Chemokines (DARC/ACKR1) can influence levels of leukocyte populations in the breast tumor environment. DARC is a nonsignaling receptor able to bind both the CC and CXC classes of chemokines, and mainly functions to modulate levels of chemokines in circulation, and aid in chemokine transport in tissues. In this regard, DARC expression may determine the profile of immune response.To investigate DARC expression and its effects on tumor-associated leukocyte (TAL) populations, we obtained RNA-seq data from The Cancer Genome Atlas (TCGA) Breast Cancer cohort. We proceeded through our analysis with those samples denoted as primary tumor samples (n=400). To estimate the relative abundance of TAL populations, we used the CIBERSORT online platform, which estimates fractions of 22 different TAL populations based on gene expression data. After completing the CIBERSORT analysis, we proceeded with only those samples that had a significant CIBERSORT output (n=167). In our analysis, we found that the total abundance of all TALs was significantly higher in tumors that have high DARC expression (p Citation Format: Rachel Martini, Brittany D. Jenkins, Clayton Yates, Lisa Newman, Melissa Davis. The Duffy Antigen Receptor for Chemokines (DARC) influences levels of tumor-associated leukocytes in the breast tumor microenvironment [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 A090.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82296398","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 A078: Dissecting the myeloid lineage in human gliomas","authors":"Claudia Z. Han, S. Duttke, Zhengyu Ouyang, S. Preissl, J. Schlachetzki, Alexander Nott, Conor Fitzpatrick, Carolyn O’Connor, N. Coufal, Mihir Gupta, D. Gonda, M. Levy, Ben-Haim Sharona, Barba David, J. Ciacci, A. Khalessi, Clark C. Chen, Bing Ren, C. Glass","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A078","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A078","url":null,"abstract":"The immune cell composition of the tumor microenvironment can be a decisive factor for tumor pathogenesis. Gliomas are tumors that develop from the glial cells of the brain and spinal cord and make up to 30% of all brain tumors. In gliomas, microglia and infiltrating macrophages can comprise up to 30 to 50% of total tumor-associated cells. Increased CD68 staining, a marker of microglia/macrophages, in adult gliomas is positively associated with histologic tumor grade. Despite the accumulated evidence substantiating a critical role for microglia and infiltrating macrophages in gliomagenesis, little is known is about the molecular mechanisms driving microglial contribution to tumor growth and whether microglia/macrophages are therapeutic targets in both low- and high-grade gliomas. Despite microglia sharing common properties with other tissue-resident macrophages, they express hundreds of genes at higher levels compared to other tissue-resident macrophages, many of which are influenced by the brain micro-environment. Additionally, engraftment of bone-marrow derived cells into the central nervous system fails to produce microglia identical to yolk sac-derived microglia at the transcriptional level. Hence, in any inflammatory context, including cancer, an interesting question arises: how does each population contribute to the pathogenesis and/or resolution of inflammation? To elucidate the role(s) of microglia/macrophages in gliomas, we isolated the myeloid fraction from primary pediatric and adult low-grade and high-grade gliomas using flow cytometry. By integrating bulk and single-cell transcriptome analysis, we find significant inter- and intratumoral heterogeneity within the myeloid population. Additionally, we find evidence for tumor environment-dependent gene change. In combination with ongoing comparative analysis of the corresponding epigenetic landscapes of the myeloid populations, we seek to decipher how the tumor microenvironment reprograms the transcription factor network in microglia/macrophages to generate tumor-promoting cells. Citation Format: Claudia Z. Han, Sascha H. Duttke, Zhengyu Ouyang, Sebastian Preissl, Johannes C.M. Schlachetzki, Alexander Nott, Conor Fitzpatrick, Carolyn O9Connor, Nicole G. Coufal, Mihir Gupta, David D. Gonda, Michael L. Levy, Ben-Haim Sharona, Barba David, Joseph D. Ciacci, Alexander A. Khalessi, Clark C. Chen, Bing Ren, Christopher K. Glass. Dissecting the myeloid lineage in human gliomas [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 A078.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86401626","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}