bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1480: A novel mechanism of immunosuppression via nanotube mediated mitochondrial trafficking between cancer cell and immune cell
Authors: Saha Tanmoy , Dash Chinmayee , Khiste Sachin , Sengupta Shiladitya 
Published: August 2019

Abstract
Cancer cells deploy multiple mechanisms for immune evasion. Here we report a novel mechanism of cancer cell-induced immune evasion via organelle trafficking between cancer cells and immune cells through physical nanotubes. Using high resolution scanning electron microscopy to analyze a co-culture assay of breast cancer cells and NKT cells revealed that the cancer cells and NKT cells form physical nanotube connections at early time points. Immunofluorescence imaging and quantification using flow cytometry revealed that the cancer cells rapidly hijack mitochondria from immune cells through these nanotubes. The transfer of mitochondria from immune cell to cancer cells imposes a metabolic impairment and results in a reduced population of immune cells. This is not observed in a control coculture using a Boyden chamber, where the two cell types are prevented from forming nanotubes. As the nanotubes are assembled via cytoskeletal rearrangement, we next tested whether the members of Rho-family of GTPases, Cdc42, Ral and Rac are involved in the actin polymerization. Indeed, an inhibitor for Cdc42/Rac1 GTPase inhibitor (ML141) and a geranylgeranyltransferase 1 inhibitor (L-778,123) significantly decreased mitochondrial transfer, and prevented the depletion of NKT cells in co-culture. Furthermore, treating 4T1 tumor-bearing animals with a combination of L-778,123 and a PD1 immune checkpoint inhibitor increased the anti-tumor efficacy compared to PD1 inhibition alone.
Conclusion: Our study sheds insights on a novel mechanism of cancer immune suppression via nanotube-mediated intercellular organelle trafficking. The efficacy of GTPase- or geranylgeranyltransferase-inhibitors, in perturbing this process, and the increased efficacy of the combination with PD1 inhibitor, opens up the possibility of developing these as novel immunotherapy agents for cancer.
Citation Format: Tanmoy Saha, Chinmayee Dash, Sachin Khiste, Shiladitya Sengupta. A novel mechanism of immunosuppression via nanotube mediated mitochondrial trafficking between cancer cell and immune cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1480.
Abstract 1486: The immune atlas and chemokine profile of giant cell tumor of bone
Authors: Li Binghao , Wang Zhan , Ye Zhaoming 
Published: August 2019

Abstract
Background and purpose: Giant cell tumor of bone (GCTB) is a locally aggressive tumor with metastatic potential. Given that GCTBs are composed of three major cell populations and the bone-resorption activity is attributed to the multinucleated giant cells which are conjectured to be recruited by “real” tumor cells, it is still elusive that how and what are these immune cells recruited. The purpose of this study is to present the immune landscape of GCTB, as well as to find out responsible chemokines during immune cell recruiting.
Experimental procedures: We collected fresh GCTB tissues from surgical excisions. To identify immune cell composition within the tumor microenvironment, we performed mass cytometry (CyTOF) and conventional multicolor cytometry. Some fresh osteosarcoma and chondrosarcoma samples were also used to compare the immune atlas. For chemokine profiling, chemokine arrays were utilized. Further analysis on potential association between chemokines and immune cells were conducted.
Results: For last updated, 47 GCTB fresh samples were collected, of which 12 cases received CyTOF analysis and the rest 35 samples were analyzed by multicolor cytometry. All GCTB samples were analyzed by chemokine array In-depth interrogation of the immune landscapes showed that compared with osteosarcoma and chondrosarcoma, GCTBs had some unique immune cell subgroups. Some CD163+ CD206+ macrophage clusters which expressed various immune suppressive markers were significantly enriched in GCTBs, while CD4+ CD25+ Treg cells were fewer in GCTB. In addition, some macrophage-like mononuclear cells (CD14- CD68+ CD163- CD206+ HLA-DR+) were only seen in GCTBs.Chemokine array revealed that higher levels of CXCL12, CCL22, and CCL7 might be associated with moremacrophage-like mononuclear cells in GCTBs.
Conclusion: GCTB have very different immune features from other malignant bone tumors. Multiple chemokines may play important roles in recruiting “functional” monocytes. Such in-depth understanding has important implications in appropriate therapeutics for GCTB. Bigger sample size will further help in studying the immune and chemokine features of GCTB.
Note: This abstract was not presented at the meeting.
Citation Format: Binghao Li, Zhan Wang, Zhaoming Ye. The immune atlas and chemokine profile of giant cell tumor of bone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1486.
Abstract 1496: Novel hCD3e mouse models for preclinical pharmacology studies of therapeutic bi-specific antibodies
Authors: Xiang Jie , Li Yanan , Shen Yuelei , Guo Yanan 
Published: August 2019

Abstract
Recently it has been demonstrated that T cell-mediated immunotherapy is an attractive treatment strategy for various diseases. For this therapeutic approach, the CD3 complex is one of the key targets to modulate T cell activation; however, in many instances we cannot directly evaluate antibody candidates in mice because the monoclonal antibodies specific to human CD3 cannot cross-react to mouse endogenous CD3. In order to overcome the current model limitation, we have generated CD3e-extracellular domain KI mice for anti-human CD3e bispecific antibody in vivo efficacy evaluation. In this model, the mouse CD3e extracellular domain was replaced by human CD3e. We used conventional mouse ES/HR technology to knock-in human CD3e genomic DNA from the 3’ end of exon 2 to the 5’ end of exon7 to replace murine exon 2-exon 6. CD3e is one of four subunits of the CD3 co-receptor, which plays an important role in the immune response, associating with the T cell receptor (TCR) to couple antigen recognition to intracellular signal transduction, leading to T cell activation. We have characterized our B-hCD3e mice with the following features:
1.Mouse CD3e+ cells were detected in the wildtype C57BL/6 mice, while human CD3e+ cells were only detected in the homozygous B-hCD3e mice.
2.T cell development was normal in B-hCD3e homozygous mice.
3.T cell subtypes in the spleen, thymus, lymph nodes, and PBMC in B-hCD3e mice were similar and comparable to that in wildtype C57BL/6 mice.
4.Normal in vitro T cell proliferation and cytokine production were found in anti-hCD3e antibody treated humanized B-hCD3e mice
5.Mouse anti-PD-1 antibody can significantly repress the growth of MC38 tumor cells engrafted on B-hCD3e mice, suggesting that T cells in B-hCD3e mice are functionally normal
6.Treatment of B-hCD3e mice with anti-human CD3e antibody OKT leads to T cell depletion, resulting in more aggressive tumor growth.
Furthermore, efficacy and toxicity evaluation of CD3e based bispecific antibodies in B-hCD3e mice are ongoing. Based on our data from extensive phenotypical analyses of B-hCD3e mice, we believe this novel humanized CD3e mouse model will be very useful for in vivo efficacy studies of CD3- mediated therapy, especially anti-CD3e bi-specific antibodies.
Citation Format: Jie Xiang, Yanan Li, Yuelei Shen, Yanan Guo. Novel hCD3e mouse models for preclinical pharmacology studies of therapeutic bi-specific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1496.
Abstract 1504: Characterization of a MC38 mouse syngeneic tumor model expressing human PD-L1 in the transgenic C57BL/6 mouse system expressing human PD-1 and PD-L1
Authors: Koratich Michael , Green Ted , Liu Jie , Hammond Charlotte , Durbin LaJuana , Zhou Jerry , Chen Anna , Stackhouse Murray 
Published: August 2019

Abstract
The human checkpoint targets PD-1 and PDL-1 continue to demonstrate great promise in the clinic. With much of the current focus turning toward combination regiments, an animal model using the human clinical antibodies will be beneficial for evaluating new combination strategies. Here we continue characterization of a C57BL/6 transgenic mouse model expressing both the human PD-1 and PD-L1 combined with a modified murine MC38 colon tumor cell line expressing human PD-L1. Both PD-1 and PD-L1 expression of the transgenic mice were verified in ex vivo stimulated splenocytes by flow cytometry analysis. Expression of PD-L1 on the genetically modified MC38 cells was also demonstrated by flow cytometry. For in vivo efficacy evaluation, tumor-implanted mice were treated with the clinical agents nivolumab and pembrolizumab at 100 µg and atezolizumab at 1 mg on Days 3, 7, 10, and 14 post implant. Treatment with nivolumab and pembrolizumab initiated tumor regression by Day 17. Complete tumor regressions were seen at Day 28 in nivolumab, 62.5% complete regression, and pembrolizumab, 71.4% complete regression. Growth inhibition was 83.9%, 69.7%, and 95.0% on Day 28 for nivolumab, atezolizumab, and pembrolizumab, respectively, compared to the control animals. There was no significant body weight loss and no signs of toxicity in any of the treated animals. To compare the human anti-PD-1 and PD-L1 clinical agent specificity, the non-transgenic parent C57BL/6 mouse strain was implanted with the unmodified MC38 colon tumor cells. Treatment with pembrolizumab and atezolizumab was conducted as with the transgenic animals. Through 28 days no growth inhibition, tumor size 105.9% of control, was seen in the pembrolizumab treated group, demonstrating lack of cross reactivity of the human therapeutic in the standard mouse model. Atezolizumab did demonstrate a 56.9% growth inhibition compared to controls and is consistent with the known cross reactivity of atezolizumab between human and mouse. We have shown a genetically modified MC38 colon tumor expressing human PD-L1 in transgenic mice expressing both human PD-1 and PD-L1 to be a suitable model for checkpoint inhibitor evaluation of the human form of the particular checkpoint therapeutic. Further research will involve combining each of the checkpoint antibodies with various chemotherapeutic agents.
Citation Format: Michael Koratich, Ted Green, Jie Liu, Charlotte Hammond, LaJuana Durbin, Jerry Zhou, Anna Chen, Murray Stackhouse. Characterization of a MC38 mouse syngeneic tumor model expressing human PD-L1 in the transgenic C57BL/6 mouse system expressing human PD-1 and PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1504.
Abstract 1513: PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion through the reprogramming of tumor-associated macrophages
Authors: Takahashi Hideyuki , Pathria Paulina , Shih Ann , Shepard Ryan M. , Paradise Marc A. , Varner Judith A. 
Published: August 2019

Abstract
We previously reported that macrophage PI3-kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ inhibition repolarizes tumor-associated macrophages, leading to downregulation of immune suppressive factors such as Arginase and IL10 and upregulation of IL12 and other pro-inflammatory cytokines. This results in recruitment and activation of intratumoral CD8+ T cells, as well as induction of immunological memory (Kaneda et al 2016). In the present study, we investigated the effect of PI3Kγ inhibition on T cell immune responses, including T cell memory induction and T cell exhaustion, in mouse models of head and neck squamous cell carcinomas (HNSCC). We found that Pik3cg−/− mice cleared implanted HPV+ HNSCC tumors; when re-challenged with tumor cells, these mice rapidly cleared secondary tumors and remained cancer-free. The proportion of T cells, especially CD8+ T cells, significantly increased in primary tumors from Pik3cg−/− mice. These CD8+ T cells expressed significantly more granzyme B and interferon and less T cell exhaustion markers than T cells from WT animals, indicating that PI3Kγ inhibition in macrophages results in T cell activation. We found that anti-tumor activity was transferable, as adoptive transfer of splenic T cells from Pik3cg−/− mice to naive WT mice suppressed tumor growth. Accordingly, Pik3cg−/− mice with primary or secondary tumors exhibited more splenic CD62L-CD44+ CD8+ effector memory T cells than WT mice. In summary, Pik3cg−/− mice exhibit a more activated T cell immune response and T cell memory than WT mice, resulting significant suppression of tumor growth. These results suggest that PI3Kγ-targeted therapy may activate durable T cell immune responses in patients with HNSCC.
Citation Format: Hideyuki Takahashi, Paulina Pathria, Ann Shih, Ryan M. Shepard, Marc A. Paradise, Judith A. Varner. PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion through the reprogramming of tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1513.
Abstract 1515: Removal of innate suppressors facilitates tumor-immune surveillance
Authors: Zhang Yao , Lee Christina , Diao Na , Li Liwu 
Published: August 2019

Abstract
Although tumor immune environment is increasingly recognized to be highly important during the modulation of tumorigenesis and tumor regression, the role and regulation of innate leukocytes such as neutrophils during the modulation of tumor immune environment remain controversial and less defined. In this study, we tested the hypothesis that removal of innate signaling suppressors may boost the anti-tumor immune function of innate neutrophils in vitro and in vivo. To this regard, we examined two key innate signaling suppressors Tollip and IRAK-M and their roles in modulating neutrophil anti-tumor immune functions. We observed that selective deletion of Tollip enhanced tumor immune surveillance in the AOM-DSS chemically induced colon cancer model. Tollip deficiency released the neutrophil suppression on T cell proliferation and activation. The adoptive transfer of Tollip deficient neutrophils were sufficient to transfer enhanced tumor immune surveillance and reduce tumor burden. Likewise, the study of another innate suppressor IRAK-M revealed that IRAK-M expression was up-regulated in the human patients with colorectal cancer. We also demonstrated that IRAK-M deficient mice exhibited reduced tumor burden following AOM-DSS challenge. Together, our data reveal a novel anti-tumor immune-enhancement strategy through utilizing reprogrammed neutrophils with targeted removal of innate signaling suppressors.
Citation Format: Yao Zhang, Christina Lee, Na Diao, Liwu Li. Removal of innate suppressors facilitates tumor-immune surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1515.
Abstract 1519: The impact of ICOS+ Tregs on prognosis of gastric cancer patients
Authors: Urakawa Shinya , Wada Hisashi , Mori Masaki , Doki Yuichiro 
Published: August 2019

Abstract
Background and Aim: Foxp3+ CD4+ regulatory T cells (Tregs) have a suppressive role in antitumor immunity. Among Foxp3+ CD4+ population, effector Tregs (eTregs) with highly suppressive functions are located in a subpopulation of Tregs. We have reported that ICOS has the potential as a novel marker for eTregs in gastric cancer (GC) and ICOS+ Tregs were abundant in H. pylori (HP) Ab-positive GC patients. In the present study, we investigate whether HP induce ICOS+ Tregs in GC.
Materials and Methods: Tumor-infiltrating lymphocytes (TILs), normal mucosa-infiltrating lymphocytes (NILs) and peripheral blood mononuclear cells (PBMCs) were obtained from 117 gastric cancer patients. Tregs, ICOS+ Tregs, linage- CD11c- CD123+ HLA-DR+ plasmacytoid dendritic cells (pDCs), TLR9+pDCs, ICOS-L+ pDCs were analyzed by flow cytometry and multicolor immunohistochemistry. HP Ab was analyzed by ELISA. For induction assay of ICOS+ Tregs, naïve CD4 T cells were cultured with pDCs under stimulation with TGF-β, CD3/CD28 mAbs and frozen-and-thawed HP (NCTC11637).
Results: In GC tissues, %ICOS-L in pDCs was positively correlated with %ICOS in Tregs (r2=0.52, p&lt;0.001). %TLR9 in pDCs and %ICOS-L in pDCs were significantly higher in HP Ab-positive patients than others (p=0.001 and p=0.042, respectively). %ICOS+ in Tregs was significantly higher in HP-Ab positive patients than others (p=0.020). By multicolor immunohistochemistry, a large number of ICOS/Foxp3 double positive cells were observed. In induction assay, addition of HP (NCTC11637) increased the expression of ICOS-L in pDC and induction of ICOS+ Tregs, which were suppressed by TLR9 antagonist. %ICOS+ in Tregs were significantly lower in HP-eradicated patients than others (p&lt;0.001). Interestingly, %ICOS+ in Tregs were also significantly lower in patients eradicated within four weeks before their surgical treatments (p&lt;0.001).
Conclusion: Our results indicate the induction pathway from HP to ICOS+ Tregs mediated by TLR9 and ICOS-L in pDCs. Preoperative eradication for HP may have a potential as an indirect immune therapy for gastric cancer patients.
Citation Format: Shinya Urakawa, Hisashi Wada, Masaki Mori, Yuichiro Doki. The impact of ICOS+ Tregs on prognosis of gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1519.
Abstract 1521: Tumor-produced hyaluronan contributes to the formation tolerogenic immunosuppressive microenvironment
Authors: Dominguez-Gutierrez Paul R. , Crispen Paul , Kusmartsev Sergei A. 
Published: August 2019

Abstract
Immunosuppressive ligand PD-L1 considered as a major player in mechanism of negative regulation of anti-tumor immune response and its expression is highly up-regulated in human and experimental tumors, including bladder cancer. Bladder cancer is characterized by aberrant hyaluronan metabolism resulting in increased HA production in tumor tissue. Hyaluronan or hyaluronic acid (HA) is a prominent component of tumor stroma/microenvironment. Membrane-bound or free extracellular HA favors tumor progression by inducing tumor cell motility, invasive properties, proliferation, production of growth factors and epithelial-mesenchymal transition. Here, we provide evidence that tumor-produced hyaluronan, one of the key tumor stroma components, contributes to the formation of tolerogenic/immunosuppressive tumor microenvironment and stimulated PD-L1 expression. We found that tumor-derived HA specifically binds to CD44 receptor expressed by myeloid precursors, such as myeloid-derived suppressor cells (MDSCs) and promotes its expansion with differentiation toward PD-L1-expressing F4/80+ macrophages. Inhibition of HA synthesis in tumor cells with pharmacologic inhibitor 4-MU, or blockade of CD44 signaling in myeloid cells with antagonistic anti-CD44 antibody, prevented the macrophage differentiation and tumor-induced up-regulation of PD-L1 expression. We also found that tumor-derived HA stimulated production of immunosuppressive and inflammatory factors IL-6, IL-10, TNF-alpha, IL-1beta and PGE2 by myeloid cells in CD44-dependent manner. Moreover, tumor-produced HA stimulated development of PD-L1-expressing macrophages in both murine and human myeloid cells. Our study reveals that tumors may evade the immune system by creating a protective tolerogenic “shield” in the form of tumor-produced HA, which binds to the CD44-expressing tumor-recruited MDSCs, stimulating production of immunosuppressive factors and promoting development of the PD-L1+ macrophages. Inhibiting of hyaluronan synthesis by tumors or targeting HA-CD44 signaling could provide an attractive approach to break tumor-induced immune tolerance and unleash the anti-tumor immune response.
Citation Format: Paul R. Dominguez-Gutierrez, Paul Crispen, Sergei A. Kusmartsev. Tumor-produced hyaluronan contributes to the formation tolerogenic immunosuppressive microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1521.
Abstract 1523: Inhibition of SUMOylation by TAK-981 induces antitumor innate immune responses by modulating macrophage and NK cell function through Type I IFN pathway activation
Authors: Nakamura Akito , Grossman Stephen , Song Keli , Idamakanti Neeraja , Shapiro Gary , Huszar Dennis 
Published: August 2019

Abstract
TAK-981 is a novel and selective small molecule inhibitor of the small ubiquitin-like modifier (SUMO) ylation enzymatic cascade in Phase 1 clinical trials. SUMOylation is a reversible post-translational modification that regulates protein function by covalent attachment of a SUMO protein to protein substrates. We have found that in vivo inhibition with TAK-981 promotes an antitumor immune response characterized by induction of a Type I interferon (IFN) response in immune cells. Interestingly, others have also reported a role for SUMOylation in restraining Type I IFN responses, upon exposure to pathogenic stimuli, using genetic approaches to inhibit SUMOylation. In this study, we demonstrate that inhibition of SUMOylation with TAK-981 enhances antitumor innate immunity by modulating macrophage and NK cell function. In vitro studies revealed that TAK-981 treatment increased expression of pro-inflammatory markers and prevented expression of anti-inflammatory markers on macrophages. TAK-981 treatment of macrophages further resulted in potent phagocytic activity against cancer cells. TAK-981 also induced expression of activation markers on NK cells and enhanced cell killing activity against cancer cells. Enhancement of macrophage phagocytosis and NK cell cytotoxicity by TAK-981 were shown to be dependent on Type I IFN receptor signaling, and both activities against CD20-positive cancer cells were further enhanced in the presence of the anti-CD20 therapeutic monoclonal antibody rituximab. Evaluation of combination activity in vivo in CD20-positive lymphoma xenograft models demonstrated synergistic antitumor activity in multiple models when TAK-981 was combined with rituximab. Inhibiting SUMOylation with TAK-981 appears to represent a novel and mechanistically unique means to the end of leveraging the potential of Type I IFNs to promote antitumor immune responses.
Citation Format: Akito Nakamura, Stephen Grossman, Keli Song, Neeraja Idamakanti, Gary Shapiro, Dennis Huszar. Inhibition of SUMOylation by TAK-981 induces antitumor innate immune responses by modulating macrophage and NK cell function through Type I IFN pathway activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1523.