bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A59: Targeting the glutamine dependent hexosamine biosynthesis pathway sensitizes pancreatic tumors to anti-PD1 therapy
Authors: Sharma Nikita S. , Gupta Vineet K. , Hadad Roey , Giri Bhuwan , Ferrantella Anthony , Dudeja Vikas , Saluja Ashok K. , Banerjee Sulagna 
Published: June 2021

Abstract
Background: Pancreatic cancer is notoriously difficult to treat owing to its late detection, metastasis and increased therapeutic resistance, leading to a 5-year survival rate of 9%. Immune evasive microenvironment further contributes to challenges in developing viable therapy options. As a result, anti-PD-1 therapy that has shown promising results in various cancers like melanoma, non-small cell lung cancer and kidney cancer is ineffective against pancreatic cancer patients. Hexosamine biosynthesis pathway (HBP), a glutamine-dependent metabolic shunt pathway responsible for producing UDP-GlcNAc and thus glycosylation, is overexpressed in pancreatic cancer. Our study shows that targeting HBP by a glutamine analog DON in pancreatic cancer can sensitize it to anti-PD1 immune therapy.
Methods: All experiments were done using primary cells isolated from spontaneous pancreatic cancer mice, KrasLSL.G12D/+; p53R172H/+; PdxCretg/+ (KPC), which are the epithelial cancer cells and the cancer-associated fibroblasts (CAFs) isolated from the same mice. 6-Diazo-5-oxo-L-norleucine (DON) was used as an inhibitor of GFAT, the rate-limiting enzyme of HBP. DON was used at a dose of 1mg/kg alone or 0.5mg/kg in combination with PD1 (100 microgm).
Results: Our study showed mice orthotopically implanted with KPC and CAF cells at a ratio of 1:9 showed a marked decrease in tumor volume when treated with DON. In addition to a decrease in tumor volume, these mice also had a profound decrease in their circulating tumor cells and a significant reduction in the collagen content in the tumor while the stromal content remained unaffected. Mice treated with low-dose DON in combination with low-dose anti-PD1 therapy showed a pronounced decrease in tumor volume as compared to either treatments alone. As expected, mice treated with the DON+PD1 combination had an increased infiltration of CD4 and CD8 cells.
Conclusion: Our study highlights for the first time an impressive response to PD1 therapy in pancreatic cancer when given in combination with DON, a glutamine analog. Since PDL1 depends on the HBP pathway for its glycosylation, inhibition by DON and the subsequent internalization of PDL1 leads to an increased immune response against pancreatic cancer that can be targeted therapeutically.
Note: This abstract was not presented at the conference.
Citation Format: Nikita S. Sharma, Vineet K. Gupta, Roey Hadad, Bhuwan Giri, Anthony Ferrantella, Vikas Dudeja, Ashok K. Saluja, Sulagna Banerjee. Targeting the glutamine dependent hexosamine biosynthesis pathway sensitizes pancreatic tumors to anti-PD1 therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A59.
Abstract A60: Targeted disruption of PI3K/Akt/mTOR signaling pathway induces cell cycle arrest, apoptosis, and autophagy, and inhibits inflammation, invasion and angiogenesis of OSCC cells
Authors: Aggarwal Sadhna , John Sarah , Sharma Suresh C. , Das Satya N. 
Published: June 2021

Abstract
Purpose: The phosphoinositide-3-kinase (PI3K) pathway is frequently altered in human cancer. This has led to the development and study of novel PI3K inhibitors for targeted therapy and also to overcome resistance to radiotherapy.
Method: The antitumor effects of PI3K inhibitors (PI-828, PI-103 and PX-866) in terms of cell proliferation, colony formation, induction of apoptosis, cell cycle arrest, invasion, autophagy, and pNF-κB/p65 translocation in SCC-4, SCC-9 and SCC-25 cells was studied by performing MTT, clonogenic, DAPI staining, propidium iodide staining, annexin-V binding, Matrigel invasion, acridine orange staining and immunofluorescence assay. Western blot assay was performed to assess the alteration in the expression of various proteins.
Results: PI-828 and PI-103 treatment exhibited dose-dependent inhibition of growth and proliferation of OSCC cells with a concomitant induction of apoptosis, altered cell cycle regulation and decreased invasiveness (p &lt;0.01). PX-866 induced apoptosis, cell cycle arrest, autophagy and a significant decrease in the invasiveness of oral cancer cells as compared to untreated cells (p &lt;0.01). These compounds significantly reduced expression of COX-2, Cyclin-D and VEGF in the treated cells besides cytoplasmic accumulation of pNF-κB/p65 protein. In addition to PI3Kα, inactivation of downstream components, i.e., Akt and mTOR, was seen.
Conclusion: PI3K inhibitors such as PI-103, PI-828 and PX-866 may be developed as potential chemotherapeutic agents for effective treatment of OSCC and other malignancies associated with activated PI3K/Akt pathway.
Note: This abstract was not presented at the conference.
Citation Format: Sadhna Aggarwal, Sarah John, Suresh C. Sharma, Satya N. Das. Targeted disruption of PI3K/Akt/mTOR signaling pathway induces cell cycle arrest, apoptosis, and autophagy, and inhibits inflammation, invasion and angiogenesis of OSCC cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A60.
Abstract A63: Commensal microbiota promote lung tumorigenesis via γδ T cells
Authors: Jin Chengcheng , Zhao Chen , Lagoudas Georgia , Bhutkar Arjun , Hu Bo , Jacks Tyler 
Published: June 2021

Abstract
Lung cancer is closely associated with chronic inflammation, but the mechanisms underlying inflammation in this setting have not been clearly defined nor have the specific contributions of particular immune cell types been elucidated. The lung is a mucosal tissue colonized by a diverse bacterial community, and pulmonary infections commonly present in lung cancer patients are linked to clinical outcomes. Here we provide evidence that local microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident γδT cells. Germ-free or antibiotic-treated mice were significantly protected from lung tumor initiation and progression induced by Kras mutation and p53 loss. Mechanistically, commensal bacteria stimulated Myd88-dependent IL-1β and IL-23 production from myeloid cells, inducing proliferation and activation of Vγ6+Vδ1+ γδ T cells that produced IL-17 and other effector molecules to promote inflammation and tumor cell proliferation. Our findings clearly link local microbiota-immune crosstalk to lung tumorigenesis, and thereby define key cellular and molecular mediators that may serve as effective targets in lung cancer treatment and prevention.
Citation Format: Chengcheng Jin, Chen Zhao, Georgia Lagoudas, Arjun Bhutkar, Bo Hu, Tyler Jacks. Commensal microbiota promote lung tumorigenesis via γδ T cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A63.
Abstract A67: Microbial polyamines and early detection of pancreatic cancer
Authors: Mendez Roberto , Kesh Kousik , Arora Nivedita , Di Martino Leá , McAllister Florencia , Merchant Nipun , Banerjee Sulagna , Banerjee Santanu 
Published: June 2021

Abstract
The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated to the abysmal survival rate in patients. In addition to several potential detection tools under active investigation, we present the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high risk for PDAC. A combination of 16s pyrosequencing and whole-genome sequencing of gut microbiota in a spontaneous genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC) showed a progressive Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were found to be significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation, validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentration. Therefore, at the early stages of tumorigenesis, the gut microbial composition changes in a way to promote inflammation and release metabolites that foster host tumorigenesis, thereby fulfilling the “vicious cycle hypothesis” of the role of the microbiome in health and disease states. Our results provide a potential, precise, noninvasive tool for early detection of PDAC, which will result in improved outcomes.
Citation Format: Roberto Mendez, Kousik Kesh, Nivedita Arora, Leá Di Martino, Florencia McAllister, Nipun Merchant, Sulagna Banerjee, Santanu Banerjee. Microbial polyamines and early detection of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A67.
Abstract A72: IFNAR1 signaling regulates PMN-MDSCs immune suppressive activity in cancer
Authors: Fuchs Serge , Alicea-Torres Kevin M. , Gabrilovich Dmitry I. 
Published: June 2021

Abstract
Polymorphnuclear myeloid-derived suppressor cells (PMN-MDSCs) are a subset of MDSCs that are expanded and accumulated in several cancers. The main role of PMN-MDSCs in cancer is the suppression of antitumor immune responses, which leads to tumor progression, angiogenesis and metastasis. PMN-MDSCs within the tumor microenvironment (TME) have potent immune-suppressive effects compared to PMN-MDSCs in peripheral organs. However, the mechanism regulating the immune-suppressive activity of PMN-MDSCs within the TME remain poorly understood. Recently, it was shown that PMN-MDSCs from spleen of tumor-bearing mice treated with type 1 interferon (IFN1) have a decrease in their immune-suppressive activity. It has been established that tumor-associated PMN-MDSCs are more suppressive than those residing in the spleen; however, their response to IFN1 remains unclear. Therefore, our goal is to understand the role of IFN1 in the regulation of PMN-MDSCs’ function within the TME. We found that IFN1 receptor, IFNAR1, is downregulated in tumor-associated PMN-MDSCs compared to their counterparts in the spleen. In cancer patients IFNAR1 on PMN-MDSC was substantially lower than on neutrophils from healthy donors. IFNAR1 downregulation in PMN-MDSCs correlated with their immune-suppressive activity. To understand the importance of IFNAR1 signaling in PMN-MDSC biology, we utilized a knock-in mouse expressing a mutant form of IFNAR1 (Ifnar1SA) that is resistant to downregulation upon stimuli and stress. PMN-MDSCs from Ifnar1SA mice were defective in their immune-suppressive activity whereas PMN-MDSCs from Ifnar1-/- mice are as immunosuppressive as PMN-MDSCs from WT mice. In this study, we described the possible role of IFN1 in negative regulation of PMN-MDSCs function in cancer.
Citation Format: Serge Fuchs, Kevin M. Alicea-Torres, Dmitry I. Gabrilovich. IFNAR1 signaling regulates PMN-MDSCs immune suppressive activity in cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A72.
Abstract A80: The effects of CCL3 on dendritic cell migration and immune cell activation
Authors: Schaller Teilo H. , Batich Kristen A. , Hotchkiss Kelly , Cui Xiuyu , Sanchez-Perez Luis , Sampson John H. 
Published: June 2021

Abstract
Glioblastoma (GBM) remains uniformly lethal and current therapy is ineffective and incapacitating. Standard therapies are limited by nonspecific toxicity, and the median overall survival for patients with GBM remains &lt;15 months. Immunotherapy for GBM holds significant promise, as substantial evidence suggests that T cells can eradicate large, well-established tumors in mice and humans. Dendritic cell (DC) vaccines can, in some cases, effectively stimulate such T-cell responses as shown by several remarkable cases of individual patient responders. However, overall objective responses in early-phase clinical trials with tumor-targeted DC vaccination have remained under 15%. In a recent study in patients with newly diagnosed GBM published in Nature, we demonstrated that unilaterally preconditioning one vaccine site with the inflammatory recall antigens Tetanus/diphtheria toxoid (Td) resulted in increased bilateral DC migration to the draining lymph nodes and a significant increase in progression-free survival and overall survival—with half of the Td-treated patients living past 4.5 years. The benefit of vaccine site preconditioning could be recapitulated in a mouse model, as we found that Td increased DC migration to the draining lymph nodes and suppressed tumor growth in an antigen-dependent manner. In a search for potential mediators of these effects, we found that the only cytokine or chemokine significantly upregulated after Td preconditioning in both patients and mice was the chemokine (C-C motif) ligand 3 (CCL3). Furthermore, our data show that a source for CCL3 appears to be Td-specific CD4+ memory effector T cells (CD4Td-mem). In experiments where wild-type mice received either CCL3(-/-) or wild-type CD4Td-mem, DC migration was increased only in the wild-type CD4Td-mem setting, signifying that CCL3 from these cells is necessary for DC migration. Finally, we have found that exogenous CCL3 alone can enhance bilateral DC migration to the draining lymph nodes and reduce tumor growth similar to Td preconditioning, suggesting that exogenous CCL3 may be used to treat patients and increase objective responses associated with DC vaccines.
Citation Format: Teilo H. Schaller, Kristen A. Batich, Kelly Hotchkiss, Xiuyu Cui, Luis Sanchez-Perez, John H. Sampson. The effects of CCL3 on dendritic cell migration and immune cell activation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A80.
Abstract A84: B7-H3 promotes antitumor T-cell suppression via MDSCs in colorectal cancer
Authors: Jayakumar Asha , Bothwell Alfred 
Published: June 2021

Abstract
One of the mechanisms causing resistance to checkpoint inhibitor treatment is accumulation of suppressive immune cells including myeloid-derived suppressor cells (MDSCs). In CRC patients, accumulation of MDSCs correlates with poor overall survival. Among a subset of CRC patients with high mutation burden, 31.1% respond to checkpoint inhibitor treatment. This implies that targeting resistance mechanisms such as MDSCs in these CRC patients could boost the efficacy of this treatment. B7-H3 (CD279), a member of the B7 family, is expressed on myeloid cells and suppresses T-cell proliferation. Therefore, we hypothesize that B7-H3 on MDSCs could promote CRC tumor growth by suppressing cytotoxic CD8 T cells. We used polyps from ApcMin/+ mice, an intestinal tumor model and a transplantable CRC tumor model such as MC38 colon carcinoma to assess the role of B7-H3. Our findings show that B7-H3 is upregulated in ApcMin/+ polyps and is expressed on in vitro derived monocytic MDSCs (M-MDSCs). The frequency of MDSCs increased with tumor growth, indicating the close correlation between MDSCs and disease burden. Blocking B7-H3 with an antibody in MC38 tumor model significantly reduced tumor volume (control group receiving isotype antibody: 1672.2 ± 121 mm3; B7-H3 antibody treated group: 892.7 ± 36.4 mm3; p&lt;0.05). The frequency of CD4 and CD8 T cells in spleens and tumors of B7-H3 antibody-treated mice was increased, but this was not statistically significant. However, the frequency of CD8 cells producing IFNγ or granzyme B was significantly increased in tumors of B7-H3 antibody-treated mice. This shows that inhibition of B7-H3 in CRC regresses tumor growth and expands cytotoxic CD8 T cells in MC38 tumors. Previously we showed that reduction of intestinal tumors in ApcMin/+Stat6-/- mice correlated with reduced MDSCs and increased CD8 cytotoxic activity, indicating that MDSCs suppressed CD8 cells. Therefore, B7-H3 suppresses cytotoxic CD8 response in colon carcinoma, possibly by mediating the suppressive function of MDSCs. Clinical trials using dual targeting antibodies to B7-H3 and CD3 recruit T cells to kill tumor cells expressing B7-H3. However, impaired T-cell effector function by MDSCs could limit the efficacy of this therapy. Targeting B7-H3 on MDSCs could overcome resistance and boost the efficacy of combination treatments.
Citation Format: Asha Jayakumar, Alfred Bothwell. B7-H3 promotes antitumor T-cell suppression via MDSCs in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A84.
Abstract A85: The role of LAP positive immune cells in cancer
Authors: Gabriely Galina , da Cunha Andre , Rezende Rafael , Skillin Nathaniel , Kenyon Brendan , Walton Lena , Gopal Murugaiyan , Weiner Howard 
Published: June 2021

Abstract
Immunotherapy that acts by counteracting the suppressive environment established by the tumor became a very promising approach for the treatment of cancer. Regulatory immune cells promote cancer by suppressing antitumor immune responses, but there are few cell surface molecules that can specifically be targeted to neutralize their function. We characterized a regulatory T-cell population that expresses surface latency-associated peptide (LAP). LAP is an adaptor and regulator of TGF-beta, a potent immunosuppressive cytokine. An increase in LAP+ CD4 T cells has been reported in human cancer, including head and neck and colorectal cancer. To study the regulatory role of LAP+ cells in cancer, we developed a murine monoclonal anti-LAP antibody. We found that treatment with anti-LAP antibody reduces tumor growth and increases survival in various cancer models, including colon carcinoma, glioblastoma and melanoma. Anti-LAP antibody is able to block TGF-beta release from cells expressing LAP and also reduces both the number and suppressive abilities of tumor-associated LAP+ regulatory cells. Anti-LAP antibody treatment triggers a profound peripheral immune response by acting on both innate and adaptive arms of the immune system. A synergistic antitumor effect was observed by combining anti-LAP antibody with dendritic cell vaccination. To study different LAP+ immune cells on a single-cell level, we developed a 19-panel flow cytometry approach. Based on the TCGA data analysis, the expression of LAP-associated genes correlates inversely with patient survival in a number of cancers. In summary, LAP+ immune cells contribute to cancer progression, and targeting these cells for cancer treatment represents a promising immunotherapeutic approach against cancer.
Citation Format: Galina Gabriely, Andre da Cunha, Rafael Rezende, Nathaniel Skillin, Brendan Kenyon, Lena Walton, Murugaiyan Gopal, Howard Weiner. The role of LAP positive immune cells in cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A85.
Abstract A86: PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion
Authors: Takahashi Hideyuki , Pathria Paulina , Shepard Ryan , Shih Ann , Louis Tiani L. , Varner Judith A. 
Published: June 2021

Abstract
Introduction: Tumor-associated macrophages promote immunosuppressive microenvironment in head and neck squamous cell carcinoma (HNSCC). We previously reported that macrophage PI3-kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. The aim of the present study was to investigate the effect of PI3Kγ inhibition on T-cell immune response, especially on T-cell memory and exhaustion status using mouse models of HNSCC.
Materials and Methods: Wild-type (WT) or Pik3cg-/- 6- to 8-week-old male syngeneic C57Bl/6J mice were implanted with HPV+ MEER tumor cells (mouse HPV+ HNSCC cell line) by subcutaneous injection. Tumors, draining lymph nodes and spleens were isolated, then analyzed using flow cytometry or mass cytometry. Mice that completely cleared tumors were reinjected with tumor cells and tumor growth was monitored. CD90.2+ T cells or CD19+ B cells that were harvested from spleens of WT or Pik3cg-/- tumor-inoculated mice were mixed 1:1 with viable tumor cells and injected into the flanks of naive WT mice.
Results: Mice lacking PI3Kγ exhibited suppressed growth of implanted HPV+ MEER tumors. The proportion of T cells, especially CD8+ T cells, significantly increased in tumors from Pik3c-/- mice. T cells from Pik3cg-/- tumors expressed significantly more granzyme B and less T-cell exhaustion markers. The proportion of CD8+ effector memory T cells significantly increased in spleens from Pik3cg-/- mice. Mice that were implanted with both tumor cells and T cells from spleens of tumor-bearing Pik3cg-/- mice exhibited significant suppression of tumor growth. All mice that had previously cleared tumors dramatically suppressed tumor growth when rechallenged with tumor cells and remained cancer-free.
Conclusion: Pik3cg-/- mice showed more activated T-cell immune response and T-cell memory than WT, resulting in significant suppression of tumor growth. These results suggest that PI3Kγ-targeted therapy might enhance the activity of checkpoint inhibitors through the activation of T-cell immune response in patients with HNSCC.
Citation Format: Hideyuki Takahashi, Paulina Pathria, Ryan Shepard, Ann Shih, Tiani L. Louis, Judith A. Varner. PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A86.