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Daniel Sanghoon Shin, Jesse M Zaretsky, Helena Escuin-Ordinas, Angel Garcia-Diaz, Siwen Hu-Lieskovan, Anusha Kalbasi, Catherine S Grasso, Willy Hugo, Salemiz Sandoval, Davis Y Torrejon, Nicolaos Palaskas, Gabriel Abril Rodriguez, Giulia Parisi, Ariel Azhdam, Bartosz Chmielowski, Grace Cherry, Elizabeth Seja, Beata Berent-Maoz, I Peter Shintaku, Dung Thi Le, Drew M Pardoll, Luis A Diaz, Paul C Tumeh, Thomas G Graeber, Roger S Lo, Begoña Comin-Anduix, Antoni Ribas
Loss of function mutations in JAK½ can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned they may also be involved in primary resistance to anti-PD-1 therapy. JAK½ inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK½ mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway...
November 30, 2016: Cancer Discovery
Ludmila Danilova, Hao Wang, Joel Sunshine, Genevieve J Kaunitz, Tricia R Cottrell, Haiying Xu, Jessica Esandrio, Robert A Anders, Leslie Cope, Drew M Pardoll, Charles G Drake, Janis M Taube
Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade has led to remarkable and durable objective responses in a number of different tumor types. A better understanding of factors associated with the PD-1/PD-L axis expression is desirable, as it informs their potential role as prognostic and predictive biomarkers and may suggest rational treatment combinations. In the current study, we analyzed PD-L1, PD-L2, PD-1, and cytolytic activity (CYT) expression, as well as mutational density from melanoma and eight other solid tumor types using The Cancer Genome Atlas database...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
Mira A Patel, Jennifer E Kim, Debebe Theodros, Ada Tam, Esteban Velarde, Christina M Kochel, Brian Francica, Thomas R Nirschl, Ali Ghasemzadeh, Dimitrios Mathios, Sarah Harris-Bookman, Christopher C Jackson, Christina Jackson, Xiaobu Ye, Phuoc T Tran, Betty Tyler, Vladimir Coric, Mark Selby, Henry Brem, Charles G Drake, Drew M Pardoll, Michael Lim
[This corrects the article DOI: 10.1186/s40425-016-0132-2.].
2016: Journal for Immunotherapy of Cancer
Kaitlyn Sadtler, Brian W Allen, Kenneth Estrellas, Franck Housseau, Drew M Pardoll, Jennifer H Elisseeff
The immune system mediates tissue growth and homeostasis and is the first responder to injury or biomaterial implantation. Recently, it has been appreciated that immune cells play a critical role in wound healing and tissue repair and should thus be considered as potentially beneficial particularly in the context of scaffolds for regenerative medicine. Here, we present a flow cytometric analysis of cellular recruitment to tissue-derived extracellular matrix scaffolds where we quantitatively describe the infiltration and polarization of several immune subtypes including macrophages, dendritic cells, neutrophils, monocytes, T cells, and B cells...
October 13, 2016: Tissue Engineering. Part A
Benjamin V Park, Zachary T Freeman, Ali Ghasemzadeh, Michael A Chattergoon, Alleluiah Rutebemberwa, Jordana Steigner, Matthew E Winter, Thanh V Huynh, Suzanne M Sebald, Se-Jin Lee, Fan Pan, Drew M Pardoll, Andrea L Cox
: Programmed death-1 (PD-1) is a coinhibitory receptor that downregulates the activity of tumor-infiltrating lymphocytes (TIL) in cancer and of virus-specific T cells in chronic infection. The molecular mechanisms driving high PD-1 expression on TILs have not been fully investigated. We demonstrate that TGFβ1 enhances antigen-induced PD-1 expression through SMAD3-dependent, SMAD2-independent transcriptional activation in T cells in vitro and in TILs in vivo The PD-1(hi) subset seen in CD8(+) TILs is absent in Smad3-deficient tumor-specific CD8(+) TILs, resulting in enhanced cytokine production by TILs and in draining lymph nodes and antitumor activity...
December 2016: Cancer Discovery
Maria Libera Ascierto, Tracee L McMiller, Alan E Berger, Ludmila Danilova, Robert A Anders, George J Netto, Haiying Xu, Theresa S Pritchard, Jinshui Fan, Chris Cheadle, Leslie Cope, Charles G Drake, Drew M Pardoll, Janis M Taube, Suzanne L Topalian
Pretreatment tumor PD-L1 expression has been shown to correlate with response to anti-PD-1/PD-L1 therapies. Yet, most patients with PD-L1(+) tumors do not respond to treatment. The current study was undertaken to investigate mechanisms underlying the failure of PD-1-targeted therapies in patients with advanced renal cell carcinoma (RCC) whose tumors express PD-L1. Formalin-fixed, paraffin-embedded pretreatment tumor biopsies expressing PD-L1 were derived from 13 RCC patients. RNA was isolated from PD-L1(+) regions and subjected to whole genome microarray and multiplex quantitative (q)RT-PCR gene expression analysis...
September 2, 2016: Cancer Immunology Research
Huang-Yu Yang, Joseph Barbi, Chao-Yi Wu, Ying Zheng, Paolo D A Vignali, Xingmei Wu, Jin-Hui Tao, Benjamin V Park, Shashika Bandara, Lewis Novack, Xuhao Ni, Xiaoping Yang, Kwang-Yu Chang, Ren-Chin Wu, Junran Zhang, Chih-Wei Yang, Drew M Pardoll, Huabin Li, Fan Pan
Regulatory T (Treg) cells are important in maintaining self-tolerance and immune homeostasis. The Treg cell transcription factor Foxp3 works in concert with other co-regulatory molecules, including Eos, to determine the transcriptional signature and characteristic suppressive phenotype of Treg cells. Here, we report that the inflammatory cytokine interleukin-6 (IL-6) actively repressed Eos expression through microRNA-17 (miR-17). miR-17 expression increased in Treg cells in the presence of IL-6, and its expression negatively correlated with that of Eos...
July 19, 2016: Immunity
Jennifer E Kim, Mira A Patel, Antonella Mangraviti, Eileen S Kim, Debebe Theodros, Esteban Velarde, Ann Liu, Eric W Sankey, Ada Tam, Haiying Xu, Dimitrios Mathios, Christopher M Jackson, Sarah Harris-Bookman, Tomas Garzon-Muvdi, Mary Sheu, Allison M Martin, Betty M Tyler, Phuoc T Tran, Xiaobu Ye, Alessandro Olivi, Janis M Taube, Peter C Burger, Charles G Drake, Henry Brem, Drew M Pardoll, Michael Lim
PURPOSE: Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype...
June 29, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
E Thiele Orberg, H Fan, A J Tam, C M Dejea, C E Destefano Shields, S Wu, L Chung, B B Finard, X Wu, P Fathi, S Ganguly, J Fu, D M Pardoll, C L Sears, F Housseau
Enterotoxigenic Bacteroides fragilis (ETBF), a human commensal and candidate pathogen in colorectal cancer (CRC), is a potent initiator of interleukin-17 (IL-17)-dependent colon tumorigenesis in Min(Apc+/-) mice. We examined the role of IL-17 and ETBF on the differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages, which are known to promote tumorigenesis. The myeloid compartment associated with ETBF-induced colon tumorigenesis in Min mice was defined using flow cytometry and gene expression profiling...
June 15, 2016: Mucosal Immunology
Mira A Patel, Jennifer E Kim, Debebe Theodros, Ada Tam, Esteban Velarde, Christina M Kochel, Brian Francica, Thomas R Nirschl, Ali Ghasemzadeh, Dimitrios Mathios, Sarah Harris-Bookman, Christopher C Jackson, Christina Jackson, Xiaobu Ye, Phuoc T Tran, Betty Tyler, Vladimir Coric, Mark Selby, Henry Brem, Charles G Drake, Drew M Pardoll, Michael Lim
BACKGROUND: Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation. Immunotherapy has demonstrated synergistic survival effects with stereotactic radiosurgery (SRS) in murine GBM. GITR is a co-stimulatory molecule expressed constitutively on regulatory T-cells and by effector T-cells upon activation. We tested the hypothesis that anti-GITR monoclonal antibody (mAb) and SRS together would confer an immune-mediated survival benefit in glioma using the orthotopic GL261 glioma model...
2016: Journal for Immunotherapy of Cancer
Dimitrios Mathios, Jacob Ruzevick, Christopher M Jackson, Haiying Xu, Sagar R Shah, Janis M Taube, Peter C Burger, Edward F McCarthy, Alfredo Quinones-Hinojosa, Drew M Pardoll, Michael Lim
No abstract text is available yet for this article.
May 2016: Journal of Neuro-oncology
Paul T Nghiem, Shailender Bhatia, Evan J Lipson, Ragini R Kudchadkar, Natalie J Miller, Lakshmanan Annamalai, Sneha Berry, Elliot K Chartash, Adil Daud, Steven P Fling, Philip A Friedlander, Harriet M Kluger, Holbrook E Kohrt, Lisa Lundgren, Kim Margolin, Alan Mitchell, Thomas Olencki, Drew M Pardoll, Sunil A Reddy, Erica M Shantha, William H Sharfman, Elad Sharon, Lynn R Shemanski, Michi M Shinohara, Joel C Sunshine, Janis M Taube, John A Thompson, Steven M Townson, Jennifer H Yearley, Suzanne L Topalian, Martin A Cheever
BACKGROUND: Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. METHODS: In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks...
June 30, 2016: New England Journal of Medicine
Kaitlyn Sadtler, Kenneth Estrellas, Brian W Allen, Matthew T Wolf, Hongni Fan, Ada J Tam, Chirag H Patel, Brandon S Luber, Hao Wang, Kathryn R Wagner, Jonathan D Powell, Franck Housseau, Drew M Pardoll, Jennifer H Elisseeff
Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/Rictor-dependent T helper 2 pathway that guides interleukin-4-dependent macrophage polarization, which is critical for functional muscle recovery. Manipulating the adaptive immune system using biomaterials engineering may support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair...
April 15, 2016: Science
Suzanne L Topalian, Janis M Taube, Robert A Anders, Drew M Pardoll
With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests...
May 2016: Nature Reviews. Cancer
Katherine B Chiappinelli, Pamela L Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal S Rote, Leslie M Cope, Alexandra Snyder, Vladimir Makarov, Sadna Budhu, Dennis J Slamon, Jedd D Wolchok, Drew M Pardoll, Matthias W Beckmann, Cynthia A Zahnow, Taha Merghoub, Timothy A Chan, Stephen B Baylin, Reiner Strick
No abstract text is available yet for this article.
February 25, 2016: Cell
Evan J Lipson, Serena M Bagnasco, Jack Moore, Sekwon Jang, Manisha J Patel, Andrea A Zachary, Drew M Pardoll, Janis M Taube, Charles G Drake
No abstract text is available yet for this article.
March 3, 2016: New England Journal of Medicine
Franck Housseau, Shaoguang Wu, Elizabeth C Wick, Hongni Fan, Xinqun Wu, Nicolas J Llosa, Kellie N Smith, Ada Tam, Sudipto Ganguly, Jane W Wanyiri, Thevambiga Iyadorai, Ausama A Malik, April C Roslani, Jamunarani S Vadivelu, Sara Van Meerbeke, David L Huso, Drew M Pardoll, Cynthia L Sears
IL17-producing Th17 cells, generated through a STAT3-dependent mechanism, have been shown to promote carcinogenesis in many systems, including microbe-driven colon cancer. Additional sources of IL17, such as γδ T cells, become available under inflammatory conditions, but their contributions to cancer development are unclear. In this study, we modeled Th17-driven colon tumorigenesis by colonizing Min(Ap) (c+/-) mice with the human gut bacterium, enterotoxigenic Bacteroides fragilis (ETBF), to investigate the link between inflammation and colorectal cancer...
April 15, 2016: Cancer Research
Christopher M Jackson, Christina M Kochel, Christopher J Nirschl, Nicholas M Durham, Jacob Ruzevick, Angela Alme, Brian J Francica, Jimmy Elias, Andrew Daniels, Thomas W Dubensky, Peter Lauer, Dirk G Brockstedt, Emily G Baxi, Peter A Calabresi, Janis M Taube, Carlos A Pardo, Henry Brem, Drew M Pardoll, Michael Lim, Charles G Drake
PURPOSE: Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. EXPERIMENTAL DESIGN: The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGFβ secretion from microglia and in the serum and TGFβ signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells...
March 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Vince Z Beachley, Matthew T Wolf, Kaitlyn Sadtler, Srikanth S Manda, Heather Jacobs, Michael R Blatchley, Joel S Bader, Akhilesh Pandey, Drew Pardoll, Jennifer H Elisseeff
Cell and protein arrays have demonstrated remarkable utility in the high-throughput evaluation of biological responses; however, they lack the complexity of native tissue and organs. Here we spotted tissue extracellular matrix (ECM) particles as two-dimensional (2D) arrays or incorporated them with cells to generate three-dimensional (3D) cell-matrix microtissue arrays. We then investigated the responses of human stem, cancer and immune cells to tissue ECM arrays originating from 11 different tissues. We validated the 2D and 3D arrays as representative of the in vivo microenvironment by means of quantitative analysis of tissue-specific cellular responses, including matrix production, adhesion and proliferation, and morphological changes after culture...
December 2015: Nature Methods
Drew Pardoll
A number of consensuses regarding cancer immunology have recently emerged from both preclinical immunotherapy models and analysis of cancer patients. First and foremost, the natural state of endogenous tumor reactive T cells is characterized by general hyporesponsiveness or anergy. This is likely due to a number of mechanisms that tumors use to induce tolerance as they develop. While many of the newer generation vaccines can effectively transfer antigen to and activate dendritic cells, T-cell tolerance remains a major barrier that is difficult to overcome by vaccination alone...
August 2015: Seminars in Oncology
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