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

{"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":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":"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":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":"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 A086: Omental fat in ovarian cancer induces lymphangiogenesis","authors":"B. Lenoir, D. Ferber, V. Starrach, M. Suarez-Carmona, S. Schott, I. Zoernig, D. Jäger, N. Halama","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A086","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A086","url":null,"abstract":"Ovarian cancer metastasis occurs by direct multifocal seeding into the peritoneum as well as by migration through the lymphatic system. High-grade ovarian carcinoma patients often present with distant metastases. Significant risk factors for the development of those are stage, grade, and lymph node involvement. The increase of the number of lymphatic vessels seems to be implicated in ovarian tumor progression. While the tropism of ovarian cancer cells for fat is well described, the potential impact of an adipose-rich microenvironment on the dissemination of metastasis via lymphatic vessels has never been investigated. So far, in this study, we examined the effect of omental fat on lymphangiogenesis in ovarian carcinoma. For that we used a cohort of 80 ovarian cancer specimens. We observed a higher number of tumor-associated vessels and principally lymphatic vessels in ovarian cancer in contact with the omentum. These lymphatic vessels are predominantly localized along the fat tissue. A higher secretion of VEGF-C is observed in ovarian tissues containing fat compared to the ones without fat, giving a potential explanation to the observed increase of lymphatic vessels in fatty tissues. We also developed a healthy fat tissue explant culture model and treated whole tissue explants with ascites. Herein, we saw an increase of the number of adipose-derived stem cells (ADSCs). These ADSCs express lymphatic markers such as D2-40 and Lyve-1. We also observed an impact of fat supernatant on the proliferation, migration and tube formation of lymphatic endothelial cells in vitro. In conclusion, we can say that omental fat in ovarian cancer seems to have an impact on lymphangiogenesis. The close contact of ascites with fat tissue seems to lead to a differentiation of adipose-derived stem cells into lymphatic endothelial cells. Further investigations must be performed to understand the exact mechanisms underlying this phenomenon. Citation Format: Benedicte M.A. Lenoir, Dyke Ferber, Victor Starrach, Meggy Suarez-Carmona, Sarah Schott, Inka Zoernig, Dirk Jager, Niels Halama. Omental fat in ovarian cancer induces lymphangiogenesis [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 A086.","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":"76824807","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":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":"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 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":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":"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 A098: SLC12A2 as a novel “brake” on immunogenic apoptotic cell clearance","authors":"Justin S. A. Perry, Sho Morioka, C. B. Medina, Michael H. Raymond, K. Ravichandran","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A098","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A098","url":null,"abstract":"Phagocytes face a key challenge during efferocytosis – they must engulf an apoptotic cell, often similar in size, while maintaining their own cell integrity, shape, and volume. Yet little is known about phagocyte volume homeostasis during apoptotic cell clearance. To this end, we performed an unbiased transcriptomics screen designed to reveal alterations of phagocyte gene expression after engulfment of apoptotic Jurkat lymphoma cells and identified several transcriptional programs distinctly modified in engulfing phagocytes. We identified a program involving cell volume regulation and potassium/chloride flux, the latter of which is thought to underlie immunogenic responses. Disruption of one member of this cell volume program, SLC12A2, resulted in “overeating” of apoptotic JurkaT-cells by individual phagocytes and a significant increase in cell size. Importantly, we demonstrate that SLC12A2-deficient phagocytes actively engulfing apoptotic JurkaT-cells led to a downregulation of the hallmark antiinflammatory efferocytosis program and robust upregulation of a proinflammatory program. In particular, we observed robust upregulation of immunogenic programs, including a type I interferon signature, in SLC12A2-deficient engulfing phagocytes that were not observed in phagocytes over-expressing the phosphatidylserine receptor TIM4, Mechanistically, we found that the chloride-sensing kinase WNK1 and downstream kinases OSR1 and SPAK function to regulate chloride flux into engulfing phagocytes via SLC12A2, and that this pathway regulates the apoptotic JurkaT-cell “overeating” observed in SLC12A2-deficient phagocytes. Collectively, these data elucidate a novel mechanism by which phagocytes protect themselves from potentially dangerous apoptotic cell-derived inflammatory ligands and suggest that SLC12A2 serves to actively suppress immunogenic responses by phagocytes and limits the rate of corpse uptake during efferocytosis. Citation Format: Justin Shaun Arnold Perry, Sho Morioka, Christopher Medina, Michael Raymond, Kodi Ravichandran. SLC12A2 as a novel “brake” on immunogenic apoptotic cell clearance [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 A098.","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":"79906281","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 A075: A protective role for group 3 innate lymphoid cells in colitis-associated colorectal cancer","authors":"J. Goc, N. Bessman, S. Sahota, F. Laure, G. Putzel, D. Withers, J. Arthur, Manish A. Shah, Gregory F. Sonnenberg","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A075","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A075","url":null,"abstract":"Chronic inflammation is recognized as a causative factor in the development of cancer and recent paradigms suggest that microbe-driven chronic inflammation is causally associated with the development and progression of cancer in the colon. Further, recent studies in mice have implicated innate lymphoid cells (ILC) as a key cell population that regulates intestinal inflammation. Group 3 innate lymphoid cells (ILC3) are essential regulators of immunity, inflammation and tissue homeostasis in the intestine, yet their role in cancer remains poorly defined. Here, we identify that ILC3 are associated with both human and mouse colon tumors. Tumor-associated ILC3 are selectively localized within lymphoid aggregates and exhibit a unique phenotypic profile as compared with nonmalignant tissue. Critically, mice with a selective deletion of ILC3-specific MHCII exhibit a striking increased susceptibility to intestinal tissue damage and develop highly invasive and flat colorectal tumors. These data demonstrate a protective role for antigen-presenting ILC3 in the context of cancer development and progression in the intestine, and suggest that further interrogation may lead to the development of novel immunotherapeutic strategies in colon cancer. Citation Format: Jeremy Goc, Nick Bessman, Sheena Sahota, Flamar Anne Laure, Gregory Putzel, David Withers, Janelle Arthur, Manish Shah, Gregory Sonnenberg. A protective role for group 3 innate lymphoid cells in colitis-associated colorectal 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 A075.","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":"89630847","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":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":"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 A121: Single-cell transcriptomic analyses reveal heterogeneity of vascular endothelial cells in cancer models","authors":"Yu Zhu, Nicole Salazar, Kevin F. Brulois, E. Butcher","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A121","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A121","url":null,"abstract":"The immune system has demonstrated promising potential as a therapeutic target in the treatment of certain cancer types, yet in many tumors the efficacy of immunotherapies is still extremely poor. One major obstacle is the limited access of immune cells to the tumor tissue. The tumor vasculature plays critical roles in regulating the recruitment of anti-tumor immune cells and the delivery of immunotherapies to the tumor sites. These immune processes require functional specialization of endothelial cells (ECs). However, there is a major gap in our understanding of the diversity, molecular specialization, and developmental relationships of tumor-associated EC subsets. To understand the heterogeneity of tumor-associated endothelium, we performed single-cell RNA sequencing (scRNAseq) analyses on ECs isolated from mouse cancer models. scRNAseq identified several subsets of endothelium in the tumor tissue, including ECs that compose the artery, capillary, and post-capillary venules. Interestingly, within the capillary endothelial compartment, we identified an EC subset that resembles tip cells in sprouting angiogenesis and demonstrates molecular signature of stem or progenitor cells. These putative progenitor cells are dramatically expanded in tumors compared to normal tissues, and comprise both quiescent and proliferative populations. The quiescent ECs express high levels of genes coding for antiapoptotic proteins, extracellular matrix molecules, immune checkpoint molecules, monocyte/macrophage recruiting cytokines, and stem cell signaling components, such as Notch4. On the other hand, the proliferative tip-like ECs express genes coding for cyclins and cyclin-dependent kinases, DNA damage repair molecules, necroptosis machinery, and epigenetic regulators. Taken together, these data define the heterogeneity of tumor-associated endothelial cells, and reveal a putative progenitor population that gives rise to the tumor vasculature and could be targeted to improve the efficacy of immunotherapies. Citation Format: Yu Zhu, Nicole Salazar, Kevin Brulois, Eugene Butcher. Single-cell transcriptomic analyses reveal heterogeneity of vascular endothelial cells in cancer 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 A121.","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":"86922529","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":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":"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}