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https://www.readbyqxmd.com/read/28212753/the-trail-induced-cancer-secretome-promotes-a-tumor-supportive-immune-microenvironment-via-ccr2
#1
Torsten Hartwig, Antonella Montinaro, Silvia von Karstedt, Alexandra Sevko, Silvia Surinova, Ankur Chakravarthy, Lucia Taraborrelli, Peter Draber, Elodie Lafont, Frederick Arce Vargas, Mona A El-Bahrawy, Sergio A Quezada, Henning Walczak
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether and to what extent TRAIL/TRAIL-R signaling in cancer cells can affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant cancer cells is FADD dependent and identify the TRAIL-induced secretome to drive monocyte polarization to myeloid-derived suppressor cells (MDSCs) and M2-like macrophages...
February 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28134623/a-ccr4-antagonist-reverses-the-tumor-promoting-microenvironment-of-renal-cancer
#2
Chiara Berlato, Moddasar N Khan, Tiziana Schioppa, Richard Thompson, Eleni Maniati, Anne Montfort, Maryam Jangani, Monica Canosa, Hagen Kulbe, Urs B Hagemann, Alexander R Duncan, Laura Fletcher, Robert W Wilkinson, Thomas Powles, Sergio A Quezada, Frances R Balkwill
Elevated expression of the chemokine receptor CCR4 in tumors is associated with poor prognosis in several cancers. Here, we have determined that CCR4 was highly expressed in human renal cell carcinoma (RCC) biopsies and observed abnormal levels of CCR4 ligands in RCC patient plasma. An antagonistic anti-CCR4 antibody had antitumor activity in the RENCA mouse model of RCC. CCR4 inhibition did not reduce the proportion of infiltrating leukocytes in the tumor microenvironment but altered the phenotype of myeloid cells, increased NK cell and Th1 cytokine levels, and reduced immature myeloid cell infiltrate and blood chemokine levels...
January 30, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28002729/the-heterogeneity-of-ly6c-hi-monocytes-controls-their-differentiation-into-inos-macrophages-or-monocyte-derived-dendritic-cells
#3
Shinelle Menezes, Daisy Melandri, Giorgio Anselmi, Thibaut Perchet, Jakob Loschko, Juan Dubrot, Rajen Patel, Emmanuel L Gautier, Stéphanie Hugues, M Paula Longhi, Jake Y Henry, Sergio A Quezada, Grégoire Lauvau, Ana-Maria Lennon-Duménil, Enrique Gutiérrez-Martínez, Alain Bessis, Elisa Gomez-Perdiguero, Christian E Jacome-Galarza, Hannah Garner, Frederic Geissmann, Rachel Golub, Michel C Nussenzweig, Pierre Guermonprez
Inflammation triggers the differentiation of Ly6C(hi) monocytes into microbicidal macrophages or monocyte-derived dendritic cells (moDCs). Yet, it is unclear whether environmental inflammatory cues control the polarization of monocytes toward each of these fates or whether specialized monocyte progenitor subsets exist before inflammation. Here, we have shown that naive monocytes are phenotypically heterogeneous and contain an NR4A1- and Flt3L-independent, CCR2-dependent, Flt3(+)CD11c(-)MHCII(+)PU.1(hi) subset...
December 20, 2016: Immunity
https://www.readbyqxmd.com/read/28002724/too-much-of-a-good-thing-chronic-ifn-fuels-resistance-to-cancer-immunotherapy
#4
James L Reading, Sergio A Quezada
Immune checkpoint blockade (ICB) is revolutionizing cancer medicine, yet the molecular basis of resistance remains unclear. In a recent issue of Cell, Benci et al. (2016) demonstrate that sustained interferon signaling is central to the development of PD-L1-dependent and -independent resistance to ICB.
December 20, 2016: Immunity
https://www.readbyqxmd.com/read/27982126/interleukin-12-bypasses-common-gamma-chain-signalling-in-emergency-natural-killer-cell-lymphopoiesis
#5
Isabel Ohs, Maries van den Broek, Kathrin Nussbaum, Christian Münz, Sebastian J Arnold, Sergio A Quezada, Sonia Tugues, Burkhard Becher
Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122(+)CD49b(+) cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM)...
December 16, 2016: Nature Communications
https://www.readbyqxmd.com/read/27622041/immunomodulatory-antibodies-for-the-treatment-of-lymphoma-report-on-the-calym-workshop
#6
Roch Houot, Philippe Gaulard, Robert Schreiber, Ira Mellman, Olivier Lambotte, Pierre G Coulie, Thierry Fest, Alan Korman, Ronald Levy, Margaret Shipp, Karin Tarte, Holbrook Kohrt, Aurélien Marabelle, Stephen Ansell, Hervé Watier, Andrea van Elsas, Arun Balakumaran, Frederick Arce Vargas, Sergio A Quezada, Gilles Salles, Daniel Olive
In November 2015, the CALYM Carnot Institute held a 2-d workshop to discuss the current and future development of immunomodulatory antibodies for the treatment of lymphoma. Highlights from the workshop are presented in this article.
July 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27571370/large-scale-detection-of-antigen-specific-t-cells-using-peptide-mhc-i-multimers-labeled-with-dna-barcodes
#7
Amalie Kai Bentzen, Andrea Marion Marquard, Rikke Lyngaa, Sunil Kumar Saini, Sofie Ramskov, Marco Donia, Lina Such, Andrew J S Furness, Nicholas McGranahan, Rachel Rosenthal, Per Thor Straten, Zoltan Szallasi, Inge Marie Svane, Charles Swanton, Sergio A Quezada, Søren Nyboe Jakobsen, Aron Charles Eklund, Sine Reker Hadrup
Identification of the peptides recognized by individual T cells is important for understanding and treating immune-related diseases. Current cytometry-based approaches are limited to the simultaneous screening of 10-100 distinct T-cell specificities in one sample. Here we use peptide-major histocompatibility complex (MHC) multimers labeled with individual DNA barcodes to screen >1,000 peptide specificities in a single sample, and detect low-frequency CD8 T cells specific for virus- or cancer-restricted antigens...
October 2016: Nature Biotechnology
https://www.readbyqxmd.com/read/27349975/neoantigen-heterogeneity-a-key-driver-of-immune-response-and-sensitivity-to-immune-checkpoint-blockade
#8
Andrew Js Furness, Sergio A Quezada, Karl S Peggs
No abstract text is available yet for this article.
June 2016: Immunotherapy
https://www.readbyqxmd.com/read/27197251/talen-mediated-inactivation-of-pd-1-in-tumor-reactive-lymphocytes-promotes-intratumoral-t-cell-persistence-and-rejection-of-established-tumors
#9
Laurie Menger, Anna Sledzinska, Katharina Bergerhoff, Frederick Arce Vargas, Julianne Smith, Laurent Poirot, Martin Pule, Javier Hererro, Karl S Peggs, Sergio A Quezada
Despite the promising efficacy of adoptive cell therapies (ACT) in melanoma, complete response rates remain relatively low and outcomes in other cancers are less impressive. The immunosuppressive nature of the tumor microenvironment and the expression of immune-inhibitory ligands, such as PD-L1/CD274 by the tumor and stroma are considered key factors limiting efficacy. The addition of checkpoint inhibitors (CPI) to ACT protocols bypasses some mechanisms of immunosuppression, but associated toxicities remain a significant concern...
April 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/26940869/clonal-neoantigens-elicit-t-cell-immunoreactivity-and-sensitivity-to-immune-checkpoint-blockade
#10
Nicholas McGranahan, Andrew J S Furness, Rachel Rosenthal, Sofie Ramskov, Rikke Lyngaa, Sunil Kumar Saini, Mariam Jamal-Hanjani, Gareth A Wilson, Nicolai J Birkbak, Crispin T Hiley, Thomas B K Watkins, Seema Shafi, Nirupa Murugaesu, Richard Mitter, Ayse U Akarca, Joseph Linares, Teresa Marafioti, Jake Y Henry, Eliezer M Van Allen, Diana Miao, Bastian Schilling, Dirk Schadendorf, Levi A Garraway, Vladimir Makarov, Naiyer A Rizvi, Alexandra Snyder, Matthew D Hellmann, Taha Merghoub, Jedd D Wolchok, Sachet A Shukla, Catherine J Wu, Karl S Peggs, Timothy A Chan, Sine R Hadrup, Sergio A Quezada, Charles Swanton
As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+)tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1...
March 25, 2016: Science
https://www.readbyqxmd.com/read/26578451/negative-immune-checkpoints-on-t-lymphocytes-and-their-relevance-to-cancer-immunotherapy
#11
REVIEW
Anna Śledzińska, Laurie Menger, Katharina Bergerhoff, Karl S Peggs, Sergio A Quezada
The term 'inhibitory checkpoint' refers to the broad spectrum of co-receptors expressed by T cells that negatively regulate T cell activation thus playing a crucial role in maintaining peripheral self-tolerance. Co-inhibitory receptor ligands are highly expressed by a variety of malignancies allowing evasion of anti-tumour immunity. Recent studies demonstrate that manipulation of these co-inhibitory pathways can remove the immunological brakes that impede endogenous immune responses against tumours. Antibodies that block the interactions between co-inhibitory receptors and their ligands have delivered very promising clinical responses, as has been shown by recent successful trials targeting the CTLA-4 and PD-1 pathways...
December 2015: Molecular Oncology
https://www.readbyqxmd.com/read/26508783/talen-mediated-genetic-inactivation-of-the-glucocorticoid-receptor-in-cytomegalovirus-specific-t-cells
#12
Laurie Menger, Agnes Gouble, Maria A V Marzolini, Annette Pachnio, Katharina Bergerhoff, Jake Y Henry, Julianne Smith, Martin Pule, Paul Moss, Stanley R Riddell, Sergio A Quezada, Karl S Peggs
Cytomegalovirus (CMV) infection is responsible for substantial morbidity and mortality after allogeneic hematopoietic stem cell transplant. T-cell immunity is critical for control of CMV infection, and correction of the immune deficiency induced by transplant is now clinically achievable by the adoptive transfer of donor-derived CMV-specific T cells. It is notable, however, that most clinical studies of adoptive T- cell therapy exclude patients with graft-versus-host disease (GVHD) from receiving systemic corticosteroid therapy, which impairs cellular immunity...
December 24, 2015: Blood
https://www.readbyqxmd.com/read/26450984/cord-blood-t-cells-mediate-enhanced-antitumor-effects-compared-with-adult-peripheral-blood-t-cells
#13
Prashant Hiwarkar, Waseem Qasim, Ida Ricciardelli, Kimberly Gilmour, Sergio Quezada, Aurore Saudemont, Persis Amrolia, Paul Veys
Unrelated cord blood transplantation (CBT) without in vivo T-cell depletion is increasingly used to treat high-risk hematologic malignancies. Following T-replete CBT, naïve CB T cells undergo rapid peripheral expansion with memory-effector differentiation. Emerging data suggest that unrelated CBT, particularly in the context of HLA mismatch and a T-replete graft, may reduce leukemic relapse. To study the role of CB T cells in mediating graft-versus-tumor responses and dissect the underlying immune mechanisms for this, we compared the ability of HLA-mismatched CB and adult peripheral blood (PB) T cells to eliminate Epstein-Barr virus (EBV)-driven human B-cell lymphoma in a xenogeneic NOD/SCID/IL2rg(null) mouse model...
December 24, 2015: Blood
https://www.readbyqxmd.com/read/26343581/cyclooxygenase-dependent-tumor-growth-through-evasion-of-immunity
#14
Santiago Zelenay, Annemarthe G van der Veen, Jan P Böttcher, Kathryn J Snelgrove, Neil Rogers, Sophie E Acton, Probir Chakravarty, Maria Romina Girotti, Richard Marais, Sergio A Quezada, Erik Sahai, Caetano Reis e Sousa
The mechanisms by which melanoma and other cancer cells evade anti-tumor immunity remain incompletely understood. Here, we show that the growth of tumors formed by mutant Braf(V600E) mouse melanoma cells in an immunocompetent host requires their production of prostaglandin E2, which suppresses immunity and fuels tumor-promoting inflammation. Genetic ablation of cyclooxygenases (COX) or prostaglandin E synthases in Braf(V600E) mouse melanoma cells, as well as in Nras(G12D) melanoma or in breast or colorectal cancer cells, renders them susceptible to immune control and provokes a shift in the tumor inflammatory profile toward classic anti-cancer immune pathways...
September 10, 2015: Cell
https://www.readbyqxmd.com/read/26091729/fc%C3%AE-receptor-tag-team-boosts-anti-tumor-immunity
#15
COMMENT
Frederick Arce Vargas, Sergio A Quezada
Anti-tumor monoclonal antibodies eliminate tumor cells through different mechanisms including antibody-mediated cell cytotoxicity and generation of long-term anti-tumor T cell responses. In a recent publication, DiLillo and Ravetch demonstrate how this vaccinal effect is mediated by engagement of Fcγ receptors expressed on antigen-presenting cells.
July 2015: Trends in Immunology
https://www.readbyqxmd.com/read/26069249/oncogenic-transformation-can-orchestrate-immune-evasion-and-inflammation-in-human-mesenchymal-stem-cells-independently-of-extrinsic-immune-selective-pressure
#16
Alex Miranda, Juan M Funes, Nilda Sánchez, Celia M Limia, Mónica Mesa, Sergio A Quezada, Rolando Pérez, Joel de León
Immune escape is a hallmark of cancer, but whether it relies upon extrinsic immune-selective pressure or is inherently orchestrated by oncogenic pathways is unresolved. To address this question, we took advantage of an in vitro model of sequentially transformed human mesenchymal stem cells (hMSC). Neoplastic transformation in this model increased the natural immune-evasive properties of hMSC, both by reducing their immunogenicity and by increasing their capacity to inhibit mitogen-driven T-cell proliferation...
August 1, 2015: Cancer Research
https://www.readbyqxmd.com/read/25887178/lactobacillus-paracasei-cncm-i-4034-and-its-culture-supernatant-modulate-salmonella-induced-inflammation-in-a-novel-transwell-co-culture-of-human-intestinal-like-dendritic-and-caco-2-cells
#17
Miriam Bermudez-Brito, Sergio Muñoz-Quezada, Carolina Gómez-Llorente, Esther Matencio, Fernando Romero, Angel Gil
BACKGROUND: The action of probiotics has been studied in vitro in cells isolated from both mice and humans, particularly enterocytes (IECs), dendritic cells (DCs) and co-cultures of peripheral DCs and IECs. Peripheral DCs and murine DCs differ from human gut DCs, and to date there are no data on the action of any probiotic on co-cultured human IECs and human intestinal DCs. To address this issue, a novel transwell model was used. Human IECs (Caco-2 cells) grown in the upper chamber of transwell filters were co-cultured with intestinal-like human DCs grown in the basolateral compartment of the transwells...
April 1, 2015: BMC Microbiology
https://www.readbyqxmd.com/read/25828465/anti-programmed-cell-death-1-therapy-and-insulin-dependent-diabetes-a-case-report
#18
Juan Martin-Liberal, Andrew Js Furness, Kroopa Joshi, Karl S Peggs, Sergio A Quezada, James Larkin
The anti programmed cell death-1 (PD-1) antibodies pembrolizumab and nivolumab have been recently licensed by the Food and Drug Administration for the treatment of advanced melanoma. Immune checkpoint inhibitors such as these can induce endocrine adverse events but autoimmune diabetes has not been described to date. However, there is a strong preclinical rationale that supports this autoimmune toxicity. We describe for the first time the case of an adult patient who developed autoimmune diabetes likely as a consequence of PD-1 inhibition with pembrolizumab...
June 2015: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/25770293/translational-implications-of-tumor-heterogeneity
#19
REVIEW
Mariam Jamal-Hanjani, Sergio A Quezada, James Larkin, Charles Swanton
Advances in next-generation sequencing and bioinformatics have led to an unprecedented view of the cancer genome and its evolution. Genomic studies have demonstrated the complex and heterogeneous clonal landscape of tumors of different origins and the potential impact of intratumor heterogeneity on treatment response and resistance, cancer progression, and the risk of disease relapse. However, the significance of subclonal mutations, in particular mutations in driver genes, and their evolution through time and their dynamics in response to cancer therapies, is yet to be determined...
March 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/25499763/cmv-promotes-recipient-t-cell-immunity-following-reduced-intensity-t-cell-depleted-hsct-significantly-modulating-chimerism-status
#20
Rob S Sellar, Frederick Arce Vargas, Jake Y Henry, Stephanie Verfuerth, Sarah Charrot, Brendan Beaton, Ronjon Chakraverty, Sergio A Quezada, Stephen Mackinnon, Kirsty J Thomson, Karl S Peggs
Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical risk varies according to a number of factors, including recipient/donor CMV serostatus. Current dogma suggests risk is greatest in seropositive recipient (R+)/seronegative donor (D-) transplants and is exacerbated by T-cell depletion. We hypothesized that in the setting of reduced-intensity T-cell-depleted conditioning, recipient-derived CMV-specific T cells escaping deletion may contribute significantly to CMV-specific immunity and might therefore also influence chimerism status...
January 22, 2015: Blood
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