35 results on '"Gigoux M"'
Search Results
2. Abstract PD6-05: Distinct tumor microenvironments stratify triple negative breast cancer into immune subtypes
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Gruosso, T, primary, Gigoux, M, additional, Bertos, N, additional, Manem, VS, additional, Zuo, D, additional, Saleg, SM, additional, Souleimanova, M, additional, Zhao, H, additional, Johnson, RM, additional, Monette, A, additional, Muñoz Ramos, V, additional, Hallett, MT, additional, Stagg, J, additional, Lapointe, R, additional, Omeroglu, A, additional, Meterissian, S, additional, Buisseret, L, additional, Van den Eyden, G, additional, Salgado, R, additional, Guiot, M-C, additional, Haibe-Kains, B, additional, and Park, M, additional more...
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- 2018
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Catalog
3. Distinct immune microenvironments stratify triple-negative breast cancer and predict outcome
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Gruosso, T., primary, Gigoux, M., additional, Bertos, N., additional, Manem, V.S.K., additional, Guiot, M.-C., additional, Buisseret, L., additional, Salgado, R., additional, Van den Eyden, G., additional, Haibe-Kains, B., additional, and Park, M., additional more...
- Published
- 2017
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4. Abstract P4-03-08: Mechanisms of CD8+ T cell immunosuppression in triple negative breast cancer
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Gruosso, T, primary, Gigoux, M, additional, Bertos, N, additional, Zuo, D, additional, Manem, V, additional, Monette, A, additional, Lapointe, R, additional, Haibe-Kains, B, additional, and Park, M, additional more...
- Published
- 2017
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5. 50P - Distinct immune microenvironments stratify triple-negative breast cancer and predict outcome
- Author
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Gruosso, T., Gigoux, M., Bertos, N., Manem, V.S.K., Guiot, M.-C., Buisseret, L., Salgado, R., Van den Eyden, G., Haibe-Kains, B., and Park, M.
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- 2017
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6. Anestesia para el trabajo de parto
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Eugenio Canessa, B., primary, Rodrigo Añazco, G., additional, Jorge Gigoux, M., additional, and Jorge Aguilera, S., additional
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- 2014
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7. Traumatismo encéfalocraneano en niños del área suroriente de Santiago
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Cristián Clavería R, Alejandro Donoso F, Alejandro Bruhn C, Camilo Boza W, Luis Villarroel del P, Adela I, Jorge Gigoux M, and Cristián Valverde G.
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traumatismo encéfalocraneano ,Pediatrics, Perinatology and Child Health ,head trauma ,computed axial tomography ,coma ,tomografía axial computadorizada cerebral ,consciousness ,estado de conciencia - Abstract
Resumen Se describen Ics caroc'eristicas clinicas de 286 pacientes !ngresados con el diagnosttco de traumatismoencefalocraneano a un hospital pubiico del Servicio de Salud Sur Oriente de Santiago entre enero de 1 993 y abril deI 995. El puntaje de Glasgow se registrc en 26! pacientes, De acuerdo al puntaje de Glasgow al ingreso, lospacientes fueron clasificaaos como traurnatismc encefalocraneano .eve (Glasgow 13-15, n = 220), moderado(Glasgow 9-12, n = 30) o grave (Glasgow < 8, n = 31). En 181 de ellos (n = 123, 28 y 30 repectivamente| sehabian realizado tomografias axiales cerebroles. Se encontroron diferencias significativas para cada grjpo en cuantoal regis'rc de alteraciones en ;a tornograf'c [p < 0,003], necesidad de procedimientos de neurocirugia (p < 0,001),exarnen neurolocico alterado ai alta (p < 0,0001) y muerte (p < 0,01). Se encontro una relacion significative entrefractura de cranec y cke'aciones en 'as imagenes tomograficas enceralicas (p < 0,04). La escala de Glasgow, apesar de ser util en la evaluacion 'nic'cl de estos pacientes, no permite por si sola descartar una complicccion, para loque es precise corrplementarla con vigilancia clinica e instrumental est. more...
- Published
- 1997
8. Epidemiología del traumatismo encéfalocraneano en niños del área suroriente de Santiago
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Boza W, Camilo, Donoso F, Alejandro, Gigoux M, Jorge, Camus I, Adela, Bruhn C, Alejandro, Valverde G, Cristián, Clavería R, Cristián, and Villarroel del P, Luís
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traumatismo encéfalocraneano ,head trauma - Published
- 1997
9. Epidemiología del traumatismo encéfalocraneano en niños del área suroriente de Santiago
- Author
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Adela Camus I, Alejandro Donoso F, Camilo Boza W, Cristián Clavería R, Luis Villarroel del P, Jorge Gigoux M, Cristián Valverde G., and Alejandro Bruhn C
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traumatismo encéfalocraneano ,Pediatrics, Perinatology and Child Health - Abstract
Se estudiaron retrospectivamente las caracteristicas epidemiologicas del Iraurnotismo encefalocraneano en 286pacienles ingresados con ese diagnostico a un hospital general del Servicio de Solud Metropolitano Sur-Oriente deSantiago de Chile, entre enero 1993 y abril 1995. La edad promedio de los pacientes era 6,1 anos, 64,7% eran va-rones, 54,5% escolares (5 a 14 aiios), 25,2% preescoiares (2 a rnenos de 5 anos] y 20,3% lactontes (menores de 24meses). En los loctantes y preescolares el acctdente ocurrio con rnas frecuencia en el hogar [78,6% y 60% respective-menre(, en escolares en la via publica (76,7%). En los primeros la principal causa del traurnatismo fueron las caidas,en los escolares los accidentes de Iransito (65,6%). En 64,9% de los casos la consulta fue hecha en la primera hora.El estado de la conciencia al ingresar al hospital (escala de coma de Glasgow), era 1 3 a 15 punfos en 76,9% de lospacientes, 9 a 12 puntos en 10,5% de ellos e igual o menor a 8 puntos en 10,8%, proporciones que son mayoresque las descritas en otras series.(Palabras clave: traumatismo encefalocraneano.] more...
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- 1997
10. Epidemiología del traumatismo encéfalocraneano en niños del área suroriente de Santiago
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Boza W, Camilo, primary, Donoso F, Alejandro, additional, Gigoux M, Jorge, additional, Camus I, Adela, additional, Bruhn C, Alejandro, additional, Valverde G, Cristián, additional, Clavería R, Cristián, additional, and Villarroel del P, Luís, additional more...
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- 1997
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11. Traumatismo encéfalocraneano en niños del área suroriente de Santiago
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Boza W, Camilo, primary, Donoso F, Alejandro, additional, Gigoux M, Jorge, additional, I, Adela, additional, Bruhn C, Alejandro, additional, Valverde G, Cristián, additional, Clavería R, Cristian, additional, and Villarroel del P, Luís, additional more...
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- 1997
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12. Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade
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Pai, JA, primary, Hellmann, MD, additional, Sauter, JL, additional, Mattar, M, additional, Rizvi, H, additional, Woo, HJ, additional, Shah, N, additional, Ngyuen, EX, additional, Uddin, FZ, additional, Quintanal-Villalonga, A, additional, Chan, JM, additional, Manoj, P, additional, Allaj, V, additional, Baine, M, additional, Bhanot, UK, additional, Jain, M, additional, Linkov, I, additional, Meng, F, additional, Brown, D, additional, Chaft, JE, additional, Plodowski, AJ, additional, Gigoux, M, additional, Won, H, additional, Sen, T, additional, Wells, DK, additional, Donoghue, MTA, additional, de Stanchina, E, additional, Wolchok, JD, additional, Boolis, B, additional, Merghoub, T, additional, Rudin, CM, additional, Chow, A, additional, and Satpathy, AT, additional more...
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13. Correction: Multiplexed molecular imaging with surface enhanced resonance Raman scattering nanoprobes reveals immunotherapy response in mice via multichannel image segmentation.
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Andreou C, Plakas K, Berisha N, Gigoux M, Rosch LE, Mirsafavi R, Oseledchyk A, Pal S, Zamarin D, Merghoub T, Detty MR, and Kircher MF
- Abstract
Correction for 'Multiplexed molecular imaging with surface enhanced resonance Raman scattering nanoprobes reveals immunotherapy response in mice via multichannel image segmentation' by Chrysafis Andreou et al. , Nanoscale Horiz. , 2022, 7 , 1540-1552, https://doi.org/10.1039/d2nh00331g. more...
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- 2023
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14. Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.
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Pai JA, Hellmann MD, Sauter JL, Mattar M, Rizvi H, Woo HJ, Shah N, Nguyen EM, Uddin FZ, Quintanal-Villalonga A, Chan JM, Manoj P, Allaj V, Baine MK, Bhanot UK, Jain M, Linkov I, Meng F, Brown D, Chaft JE, Plodkowski AJ, Gigoux M, Won HH, Sen T, Wells DK, Donoghue MTA, de Stanchina E, Wolchok JD, Loomis B, Merghoub T, Rudin CM, Chow A, and Satpathy AT more...
- Subjects
- Humans, CD8-Positive T-Lymphocytes, Immune Checkpoint Inhibitors therapeutic use, Receptors, Antigen, T-Cell, Clone Cells, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8
+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8+ T cells are clonally linked to TCF7+ SELL+ progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones reveals persistence in the peripheral blood for years after ICB therapy., Competing Interests: Declaration of interests M.D.H. reports advisory/consulting fees from Achilles, Adagene, Adicet, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Da Volaterra, Eli Lilly, Genentech, Genzyme/Sanofi, Immunai, Instill Bio, Janssen, Mana Therapeutics, Merk, Mirati, Pact Pharma, Regeneron, Roche, and Shattuck Labs; research funding from Bristol Myers Squibb; stock interest with Arcus, Factorial, Immunai, and Shattuck Labs; a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics (PGDx); after the completion of this work, M.D.H .began as an employee (and equity holder) at AstraZeneca. J.D.W. has Equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linneaus, Georgiamune, Maverick, Tizona Pharmaceuticals, and Trieza. J.D.W. is a co-inventor on the following patent application: Xenogeneic (Canine) DNA vaccines, myeloid-derived suppressor cell (MDSC) assay, anti-PD1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, Newcastle disease viruses for cancer therapy, and prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment. J.D.W. and T.M. are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ Therapeutics. T.M. receives research funding from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus–based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, and PharmaMar and is on the scientific advisory boards of Elucida, Bridge, and Harpoon. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. The remaining authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...- Published
- 2023
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15. T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants.
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Hirschhorn D, Budhu S, Kraehenbuehl L, Gigoux M, Schröder D, Chow A, Ricca JM, Gasmi B, De Henau O, Mangarin LMB, Li Y, Hamadene L, Flamar AL, Choi H, Cortez CA, Liu C, Holland A, Schad S, Schulze I, Betof Warner A, Hollmann TJ, Arora A, Panageas KS, Rizzuto GA, Duhen R, Weinberg AD, Spencer CN, Ng D, He XY, Albrengues J, Redmond D, Egeblad M, Wolchok JD, and Merghoub T more...
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- Mice, Animals, Neutrophils pathology, Antigenic Drift and Shift, Immunotherapy, CTLA-4 Antigen, T-Lymphocytes pathology, Melanoma
- Abstract
Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4
+ T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4+ T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants., Competing Interests: Declaration of interests T.M. is a consultant for Daiichi Sankyo, Leap Therapeutics, Immunos Therapeutics, and Pfizer and co-founder of Imvaq Therapeutics. T.M. has equity in Imvaq Therapeutics. T.M. reports grants from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. D.H. and S.B. have received royalties from Agenus. R.Z. is an inventor on patent applications related to work on GITR, PD-1, and CTLA-4; has received grant support from Bristol-Myers Squibb; and is a consultant for Leap Therapeutics. J.D.W. is a consultant for Apricity, Ascentage Pharma, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Imvaq, Larkspur, Psioxus, Recepta, Tizona, and Sellas. J.D.W. received grant/research support from Bristol Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Beigene, CellCarta, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, and Xenimmune. J.D.W. is an inventor on the following patents: xenogeneic DNA vaccines, alphavirus replicon particles expressing TRP2, myeloid-derived suppressor cell (MDSC) assay, Newcastle disease virus for cancer therapy, genomic signature to identify responders to ipilimumab in melanoma, engineered vaccinia viruses for cancer immunotherapy (with T.M.), anti-CD40 agonist mAb fused to monophosphoryl lipid A (MPL) for cancer therapy (with T.M.), CAR(+) T cells targeting differentiation antigens as a means to treat cancer, anti-PD-1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies, and methods of use thereof. D.H. and T.M. are co-inventors on patent applications related to OX40 antibodies. M.E. is a member of the research advisory board for brensocatib for Insmed, Inc.; a member of the scientific advisory board for Vividion Therapeutics, Inc.; and a consultant for Protalix, Inc. and holds shares in Agios Pharmaceuticals, Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...- Published
- 2023
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16. Multiplexed molecular imaging with surface enhanced resonance Raman scattering nanoprobes reveals immunotherapy response in mice via multichannel image segmentation.
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Andreou C, Plakas K, Berisha N, Gigoux M, Rosch LE, Mirsafavi R, Oseledchyk A, Pal S, Zamarin D, Merghoub T, Detty MR, and Kircher MF
- Subjects
- Mice, Animals, Immunotherapy, Antibodies therapeutic use, Immunologic Factors, Molecular Imaging, Tumor Microenvironment, Spectrum Analysis, Raman methods, Neoplasms diagnostic imaging, Neoplasms therapy
- Abstract
Visualizing the presence and distribution of multiple specific molecular markers within a tumor can reveal the composition of its microenvironment, inform diagnosis, stratify patients, and guide treatment. Raman imaging with multiple molecularly-targeted surface enhanced Raman scattering (SERS) nanoprobes could help investigate emerging cancer treatments preclinically or enable personalized treatment assessment. Here, we report a comprehensive strategy for multiplexed imaging using SERS nanoprobes and machine learning (ML) to monitor the early effects of immune checkpoint blockade (ICB) in tumor-bearing mice. We used antibody-functionalized SERS nanoprobes to visualize 7 + 1 immunotherapy-related targets simultaneously. The multiplexed images were spectrally resolved and then spatially segmented into superpixels based on the unmixed signals. The superpixels were used to train ML models, leading to the successful classification of mice into treated and untreated groups, and identifying tumor regions with variable responses to treatment. This method may help predict treatment efficacy in tumors and identify areas of tumor variability and therapy resistance. more...
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- 2022
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17. Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine.
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Gigoux M, Holmström MO, Zappasodi R, Park JJ, Pourpe S, Bozkus CC, Mangarin LMB, Redmond D, Verma S, Schad S, George MM, Venkatesh D, Ghosh A, Hoyos D, Molvi Z, Kamaz B, Marneth AE, Duke W, Leventhal MJ, Jan M, Ho VT, Hobbs GS, Knudsen TA, Skov V, Kjær L, Larsen TS, Hansen DL, Lindsley RC, Hasselbalch H, Grauslund JH, Lisle TL, Met Ö, Wilkinson P, Greenbaum B, Sepulveda MA, Chan T, Rampal R, Andersen MH, Abdel-Wahab O, Bhardwaj N, Wolchok JD, Mullally A, and Merghoub T more...
- Subjects
- Animals, Calreticulin genetics, Humans, Janus Kinase 2 genetics, Major Histocompatibility Complex, Mice, Mice, Inbred C57BL, Mutation genetics, Peptides, Vaccines, Subunit, Cancer Vaccines, Myeloproliferative Disorders genetics, Neoplasms genetics
- Abstract
The majority of JAK2
V617F -negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin ( CALR ), resulting in a common carboxyl-terminal mutant fragment (CALRMUT ), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALRMUT -specific T cells are rare in patients with CALRMUT MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALRMUT MPN from two independent cohorts. We observed that MHC-I alleles that present CALRMUT neoepitopes with high affinity are underrepresented in patients with CALRMUT MPN. We speculated that this was due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifested. As a consequence of this MHC-I allele restriction, we reasoned that patients with CALRMUT MPN would not efficiently respond to a CALRMUT fragment cancer vaccine but would when immunized with a modified CALRMUT heteroclitic peptide vaccine approach. We found that heteroclitic CALRMUT peptides specifically designed for the MHC-I alleles of patients with CALRMUT MPN efficiently elicited a CALRMUT cross-reactive CD8+ T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALRMUT native peptides. We corroborated this effect in vivo in mice and observed that C57BL/6J mice can mount a CD8+ T cell response to the CALRMUT fragment upon immunization with a CALRMUT heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide-based cancer vaccines in patients with CALRMUT MPN. more...- Published
- 2022
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18. Tumor-induced double positive T cells display distinct lineage commitment mechanisms and functions.
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Schad SE, Chow A, Mangarin L, Pan H, Zhang J, Ceglia N, Caushi JX, Malandro N, Zappasodi R, Gigoux M, Hirschhorn D, Budhu S, Amisaki M, Arniella M, Redmond D, Chaft J, Forde PM, Gainor JF, Hellmann MD, Balachandran V, Shah S, Smith KN, Pardoll D, Elemento O, Wolchok JD, and Merghoub T more...
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- Animals, CD4 Antigens metabolism, CD8 Antigens metabolism, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Lineage genetics, Mice, T-Lymphocyte Subsets, CD4-Positive T-Lymphocytes, Melanoma metabolism
- Abstract
Transcription factors ThPOK and Runx3 regulate the differentiation of "helper" CD4+ and "cytotoxic" CD8+ T cell lineages respectively, inducing single positive (SP) T cells that enter the periphery with the expression of either the CD4 or CD8 co-receptor. Despite the expectation that these cell fates are mutually exclusive and that mature CD4+CD8+ double positive (DP) T cells are present in healthy individuals and augmented in the context of disease, yet their molecular features and pathophysiologic role are disputed. Here, we show DP T cells in murine and human tumors as a heterogenous population originating from SP T cells which re-express the opposite co-receptor and acquire features of the opposite cell type's phenotype and function following TCR stimulation. We identified distinct clonally expanded DP T cells in human melanoma and lung cancer by scRNA sequencing and demonstrated their tumor reactivity in cytotoxicity assays. Our findings indicate that antigen stimulation induces SP T cells to differentiate into DP T cell subsets gaining in polyfunctional characteristics., (© 2022 Schad et al.) more...
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- 2022
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19. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.
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Łuksza M, Sethna ZM, Rojas LA, Lihm J, Bravi B, Elhanati Y, Soares K, Amisaki M, Dobrin A, Hoyos D, Guasp P, Zebboudj A, Yu R, Chandra AK, Waters T, Odgerel Z, Leung J, Kappagantula R, Makohon-Moore A, Johns A, Gill A, Gigoux M, Wolchok J, Merghoub T, Sadelain M, Patterson E, Monasson R, Mora T, Walczak AM, Cocco S, Iacobuzio-Donahue C, Greenbaum BD, and Balachandran VP more...
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- Humans, T-Lymphocytes immunology, Tumor Escape immunology, Antigens, Neoplasm genetics, Antigens, Neoplasm immunology, Cancer Survivors, Pancreatic Neoplasms genetics, Pancreatic Neoplasms immunology, Pancreatic Neoplasms pathology
- Abstract
Cancer immunoediting
1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3 , whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features-'non-selfness' based on neoantigen similarity to known antigens4,5 , and 'selfness' based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer., (© 2022. The Author(s).) more...- Published
- 2022
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20. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity.
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Lu SX, De Neef E, Thomas JD, Sabio E, Rousseau B, Gigoux M, Knorr DA, Greenbaum B, Elhanati Y, Hogg SJ, Chow A, Ghosh A, Xie A, Zamarin D, Cui D, Erickson C, Singer M, Cho H, Wang E, Lu B, Durham BH, Shah H, Chowell D, Gabel AM, Shen Y, Liu J, Jin J, Rhodes MC, Taylor RE, Molina H, Wolchok JD, Merghoub T, Diaz LA Jr, Abdel-Wahab O, and Bradley RK more...
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- Animals, Antigen Presentation drug effects, Antigen Presentation immunology, Antigens, Neoplasm metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Epitopes immunology, Ethylenediamines pharmacology, Gene Expression Regulation, Neoplastic drug effects, Hematopoiesis drug effects, Hematopoiesis genetics, Histocompatibility Antigens Class I metabolism, Humans, Immune Checkpoint Inhibitors pharmacology, Immunotherapy, Inflammation pathology, Mice, Inbred C57BL, Peptides metabolism, Protein Isoforms metabolism, Pyrroles pharmacology, RNA Splicing drug effects, Sulfonamides pharmacology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Mice, Neoplasms genetics, Neoplasms immunology, RNA Splicing genetics
- Abstract
Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic., Competing Interests: Declaration of interests O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine, Merck, Prelude Therapeutics, and Janssen, and is on the scientific advisory board of Envisagenics, Pfizer Boulder, and AIChemy. O.A.-W. has received prior research funding from Loxo Oncology and H3 Biomedicine unrelated to this work. S.X.L. has served as a consultant (uncompensated) for PTC Therapeutics. B.R. has served as a consultant for Bayer and Roche. D.Z. reports clinical research support to his institution from Astra Zeneca, Plexxikon, and Genentech and personal/consultancy fees from Merck, Synlogic Therapeutics, Tesaro, Bristol Myers Squibb (BMS), Genentech, Xencor, Memgen, Calidi Biotherapeutics, and Agenus. L.A.D. is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics. L.A.D. is a compensated consultant to PGDx, 4Paws (PetDx), Innovatus CP, Se’er, Delfi, Kinnate, and Neophore. L.A.D. is an uncompensated consultant for, but has received clinical trial support from, Merck. L.A.D. holds equity in PGDx, Jounce, Se’er, Delfi, Kinnate, and Neophore and divested equity in Thrive Earlier Detection in 2021. His spouse holds equity in Amgen. J.D.W. is a consultant for Amgen, Apricity, Arsenal IO, Ascentage Pharma, AstraZeneca, Astellas, Boehringer Ingelheim, BMS, Chugai, Dragonfly, F Star, Eli Lilly, Georgiamune, IMVAQ, Merck, Polynoma, Psioxus, Recepta, Trieza, Truvax, Sellas, and Werewolf Therapeutics. J.D.W. has grant/research support from BMS and Sephora. J.D.W. reports equity in Tizona Pharmaceuticals, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, and Georgiamune. T.M. is an inventor on patents involving the use of anti-PD-1 antibodies. T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ. T.M. receives research funding from BMS, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. S.X.L., O.A.-W., and R.K.B. are inventors on a patent application submitted by FHCRC related to this work., (Copyright © 2021 Elsevier Inc. All rights reserved.) more...
- Published
- 2021
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21. Targeting Phosphatidylserine Enhances the Anti-tumor Response to Tumor-Directed Radiation Therapy in a Preclinical Model of Melanoma.
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Budhu S, Giese R, Gupta A, Fitzgerald K, Zappasodi R, Schad S, Hirschhorn D, Campesato LF, De Henau O, Gigoux M, Liu C, Mazo G, Deng L, Barker CA, Wolchok JD, and Merghoub T
- Subjects
- Animals, Disease Models, Animal, Humans, Melanoma pathology, Mice, Tumor Microenvironment, Melanoma radiotherapy, Phosphatidylserines metabolism
- Abstract
Phosphatidylserine (PS) is exposed on the surface of apoptotic cells and is known to promote immunosuppressive signals in the tumor microenvironment (TME). Antibodies that block PS interaction with its receptors have been shown to repolarize the TME into a proinflammatory state. Radiation therapy (RT) is an effective focal treatment of isolated solid tumors but is less effective at controlling metastatic cancers. We found that tumor-directed RT caused an increase in expression of PS on the surface of viable immune infiltrates in mouse B16 melanoma. We hypothesize that PS expression on immune cells may provide negative feedback to immune cells in the TME. Treatment with an antibody that targets PS (mch1N11) enhanced the anti-tumor efficacy of tumor-directed RT and improved overall survival. This combination led to an increase in proinflammatory tumor-associated macrophages. The addition of anti-PD-1 to RT and mch1N11 led to even greater anti-tumor efficacy and overall survival. We found increased PS expression on several immune subsets in the blood of patients with metastatic melanoma after receiving tumor-directed RT. These findings highlight the potential of combining PS targeting with RT and PD-1 pathway blockade to improve outcomes in patients with advanced-stage cancers., Competing Interests: Declaration of Interests All authors concur with the submission of this manuscript and have no financial or other interests related to the submitted work. T.M. is a cofounder and holds an equity in IMVAQ Therapeutics. He is a consultant of Immunos Therapeutics and Pfizer. He has research support from Bristol Myers Squibb; Surface Oncology; Kyn Therapeutics; Infinity Pharmaceuticals, Inc.; Peregrine Pharmaceuticals, Inc.; Adaptive Biotechnologies; Leap Therapeutics, Inc.; and Aprea. He has patents on applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. J.D.W. is a consultant for Adaptive Biotech, Advaxis, Amgen, Apricity, Array BioPharma, Ascentage Pharma, Astellas, Bayer, Beigene, Bristol Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, F Star, Genentech, Imvaq, Janssen, Kleo Pharma, Linnaeus, MedImmune, Merck, Neon Therapeutics, Ono, Polaris Pharma, Polynoma, Psioxus, Puretech, Recepta, Trieza, Sellas Life Sciences, Serametrix, Surface Oncology, and Syndax. Research support: Bristol Myers Squibb, Medimmune, Merck Pharmaceuticals, and Genentech. Equity: Potenza Therapeutics, Tizona Pharmaceuticals, Adaptive Biotechnologies, Elucida, Imvaq, Beigene, Trieza, and Linnaeus. Honorarium: Esanex. Patents: xenogeneic DNA vaccines, alphavirus replicon particles expressing TRP2, MDSC assay, Newcastle disease viruses for cancer therapy, genomic signature to identify responders to ipilimumab in melanoma, engineered vaccinia viruses for cancer immunotherapy, anti-CD40 agonist monoclonal antibody (mAb) fused to monophosphoryl lipid A (MPL) for cancer therapy, CAR+ T cells targeting differentiation antigens as means to treat cancer, anti-PD-1 antibody, anti-CTLA-4 antibodies, and anti-GITR antibodies and methods of use thereof. L.D. is a cofounder and holds equity in IMVAQ Therapeutics. She has patents on applications related to work on oncolytic viral therapy. R.Z. is inventor on patent applications related to work on GITR, PD-1, and CTLA-4. R.Z. is consultant for Leap Therapeutics and iTEOS Belgium SA. C.A.B. is a consultant of Regeneron. He has research support from Amgen and Merck., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.) more...
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- 2021
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22. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine.
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Campesato LF, Budhu S, Tchaicha J, Weng CH, Gigoux M, Cohen IJ, Redmond D, Mangarin L, Pourpe S, Liu C, Zappasodi R, Zamarin D, Cavanaugh J, Castro AC, Manfredi MG, McGovern K, Merghoub T, and Wolchok JD more...
- Subjects
- Animals, Drug Resistance, Neoplasm, Humans, Immune Tolerance, Immunotherapy, Indoleamine-Pyrrole 2,3,-Dioxygenase genetics, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Mice, Neoplasms immunology, Neoplasms therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon metabolism, Signal Transduction, Tryptophan Oxygenase genetics, Tryptophan Oxygenase metabolism, Tumor Cells, Cultured, Tumor Microenvironment, Kynurenine immunology, Macrophages immunology, Receptors, Aryl Hydrocarbon antagonists & inhibitors, T-Lymphocytes, Regulatory immunology
- Abstract
Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8
+ T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors. more...- Published
- 2020
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23. Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers.
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Gruosso T, Gigoux M, Manem VSK, Bertos N, Zuo D, Perlitch I, Saleh SMI, Zhao H, Souleimanova M, Johnson RM, Monette A, Ramos VM, Hallett MT, Stagg J, Lapointe R, Omeroglu A, Meterissian S, Buisseret L, Van den Eynden G, Salgado R, Guiot MC, Haibe-Kains B, and Park M more...
- Subjects
- B7-H1 Antigen immunology, CD8-Positive T-Lymphocytes pathology, Cholesterol immunology, Female, Granzymes immunology, Humans, Interferon Type I immunology, Triple Negative Breast Neoplasms pathology, CD8-Positive T-Lymphocytes immunology, Triple Negative Breast Neoplasms immunology, Tumor Microenvironment immunology
- Abstract
Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC, with implications for current therapies including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme B+CD8+ T cells (GzmB+CD8+ T cells), a type 1 IFN signature, and elevated expression of multiple immune inhibitory molecules including indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1), and resulted in good outcomes. An "immune-cold" microenvironment with an absence of tumoral CD8+ T cells was defined by elevated expression of the immunosuppressive marker B7-H4, signatures of fibrotic stroma, and poor outcomes. A distinct poor-outcome immunomodulatory microenvironment, hitherto poorly characterized, exhibited stromal restriction of CD8+ T cells, stromal expression of PD-L1, and enrichment for signatures of cholesterol biosynthesis. Metasignatures defining these TIME subtypes allowed us to stratify TNBCs, predict outcomes, and identify potential therapeutic targets for TNBC. more...
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- 2019
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24. Potentiating vascular-targeted photodynamic therapy through CSF-1R modulation of myeloid cells in a preclinical model of prostate cancer.
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Lebdai S, Gigoux M, Alvim R, Somma A, Nagar K, Azzouzi AR, Cussenot O, Merghoub T, Wolchok JD, Scherz A, Kim K, and Coleman J
- Abstract
Vascular-targeted photodynamic therapy (VTP) induces rapid destruction of targeted tissues and is a promising therapy for prostate cancer. However, the resulting immune response, which may play an important role in either potentiating or blunting the effects of VTP, is still incompletely understood. Myeloid cells such as myeloid-derived suppressor cells (MDSCs) and macrophages are often found in tumors and are widely reported to be associated with cancer angiogenesis, tissue remodeling, and immunosuppression. These cells are also known to play a critical role in wound-healing, which is induced by rapid tissue destruction. In this study, we investigated the effects of VTP on the recruitment of tumor-infiltrating myeloid cells, specifically MDSCs and tumor-associated macrophages (TAMs), in the Myc-Cap and TRAMP C2 murine prostate cancer models. We report that VTP increased the infiltration of myeloid cells into the tumors, as well as their expression of CSF1R, a receptor required for myeloid differentiation, proliferation, and tumor migration. As anti-CSF1R treatment has previously been used to deplete these cells types in other murine models of prostate cancer, we hypothesized that combining anti-CSF1R with VTP therapy would lead to decreased tumor regrowth and improved survival. Importantly, we found that targeting myeloid cells using anti-CSF1R in combination with VTP therapy decreased the number of tumor MDSCs and TAMs, especially M2 macrophages, as well as increased CD8
+ T cell infiltration, decreased tumor growth and improved overall survival. These results suggest that targeting myeloid cells via CSF1R targeting is a promising strategy to potentiate the anti-tumor effects of VTP. more...- Published
- 2019
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25. PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy.
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Zamarin D, Ricca JM, Sadekova S, Oseledchyk A, Yu Y, Blumenschein WM, Wong J, Gigoux M, Merghoub T, and Wolchok JD
- Published
- 2018
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26. Refusing to TAP out: 16 new human TEIPPs identified.
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Gigoux M and Wolchok J
- Subjects
- Humans, Antigens, Neoplasm, Neoplasms
- Abstract
In this issue of JEM , Marijt et al. (https://doi.org/10.1084/jem.20180577) report their discovery of 16 novel human TAP-independent TEIPP peptides, whereas only one had been previously identified. This opens the door to new therapeutic options for patients with TAP-deficient tumors., (© 2018 Gigoux and Wolchok.) more...
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- 2018
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27. Lysis-independent potentiation of immune checkpoint blockade by oncolytic virus.
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Oseledchyk A, Ricca JM, Gigoux M, Ko B, Redelman-Sidi G, Walther T, Liu C, Iyer G, Merghoub T, Wolchok JD, and Zamarin D
- Abstract
Intratumoral therapy with oncolytic viruses is increasingly being explored as a strategy to potentiate an immune response against cancer, but it remains unknown whether such therapy should be restricted to cancers sensitive to virus-mediated lysis. Using Newcastle Disease Virus (NDV) as a model, we explore immunogenic potential of an oncolytic virus in bladder cancer, where existing immunotherapy with PD-1 and PD-L1-targeting antibodies to date has shown suboptimal response rates. Infection of human and mouse bladder cancer cells with NDV resulted in immunogenic cell death, activation of innate immune pathways, and upregulation of MHC and PD-L1 in all tested cell lines, including the cell lines completely resistant to NDV-mediated lysis. In a bilateral flank NDV-lysis-resistant syngeneic murine bladder cancer model, intratumoral therapy with NDV led to an increase of immune infiltration in both treated and distant tumors and a shift from an inhibitory to effector T cell phenotype. Consequently, combination of intratumoral NDV with systemic PD-1 or CTLA-4 blockade led to improved local and abscopal tumor control and overall survival. These findings encourage future clinical trials combining intratumoral NDV therapy with systemic immunomodulatory agents and underscore the rationale for such treatments irrespective of tumor cell sensitivity to NDV-mediated lysis., Competing Interests: CONFLICTS OF INTEREST D.Z. and J.D.W. are inventors on a patent concerning the uses of recombinant Newcastle Disease Virus for cancer therapy. more...
- Published
- 2018
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28. CrosstalkNet: A Visualization Tool for Differential Co-expression Networks and Communities.
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Manem V, Adam GA, Gruosso T, Gigoux M, Bertos N, Park M, and Haibe-Kains B
- Subjects
- Algorithms, Breast Neoplasms genetics, Female, Humans, Software Design, Gene Expression Profiling, Gene Regulatory Networks
- Abstract
Variations in physiological conditions can rewire molecular interactions between biological compartments, which can yield novel insights into gain or loss of interactions specific to perturbations of interest. Networks are a promising tool to elucidate intercellular interactions, yet exploration of these large-scale networks remains a challenge due to their high dimensionality. To retrieve and mine interactions, we developed CrosstalkNet, a user friendly, web-based network visualization tool that provides a statistical framework to infer condition-specific interactions coupled with a community detection algorithm for bipartite graphs to identify significantly dense subnetworks. As a case study, we used CrosstalkNet to mine a set of 54 and 22 gene-expression profiles from breast tumor and normal samples, respectively, with epithelial and stromal compartments extracted via laser microdissection. We show how CrosstalkNet can be used to explore large-scale co-expression networks and to obtain insights into the biological processes that govern cross-talk between different tumor compartments. Significance: This web application enables researchers to mine complex networks and to decipher novel biological processes in tumor epithelial-stroma cross-talk as well as in other studies of intercompartmental interactions. Cancer Res; 78(8); 2140-3. ©2018 AACR ., (©2018 American Association for Cancer Research.) more...
- Published
- 2018
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29. Identification of Interacting Stromal Axes in Triple-Negative Breast Cancer.
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Saleh SMI, Bertos N, Gruosso T, Gigoux M, Souleimanova M, Zhao H, Omeroglu A, Hallett MT, and Park M
- Subjects
- B-Lymphocytes pathology, Epithelial Cells pathology, Female, Humans, Prognosis, T-Lymphocytes pathology, B-Lymphocytes metabolism, Biomarkers, Tumor metabolism, Epithelial Cells metabolism, T-Lymphocytes metabolism, Transcriptome, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology
- Abstract
Triple-negative breast cancer (TNBC) is a molecularly heterogeneous cancer that is difficult to treat. Despite the role it may play in tumor progression and response to therapy, microenvironmental (stromal) heterogeneity in TNBC has not been well characterized. To address this challenge, we investigated the transcriptome of tumor-associated stroma isolated from TNBC ( n = 57). We identified four stromal axes enriched for T cells (T), B cells (B), epithelial markers (E), or desmoplasia (D). Our analysis method (STROMA4) assigns a score along each stromal axis for each patient and then combined the axis scores to subtype patients. Analysis of these subtypes revealed that prognostic capacity of the B, T, and E scores was governed by the D score. When compared with a previously published TNBC subtyping scheme, the STROMA4 method better captured tumor heterogeneity and predicted patient benefit from therapy with increased sensitivity. This approach produces a simple ontology that captures TNBC heterogeneity and informs how tumor-associated properties interact to affect prognosis. Cancer Res; 77(17); 4673-83. ©2017 AACR ., (©2017 American Association for Cancer Research.) more...
- Published
- 2017
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30. Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination.
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Rashkovan M, Vadnais C, Ross J, Gigoux M, Suh WK, Gu W, Kosan C, and Möröy T
- Subjects
- Analysis of Variance, Animals, Cell Death physiology, Chromatin Immunoprecipitation, Flow Cytometry, Gene Expression Regulation genetics, Genetic Vectors genetics, Immunoblotting, Immunoprecipitation, Mice, Mice, Inbred C57BL, Nuclear Proteins genetics, Protein Biosynthesis genetics, Protein Inhibitors of Activated STAT genetics, Real-Time Polymerase Chain Reaction, Ubiquitin-Protein Ligases, V(D)J Recombination physiology, Gene Expression Regulation physiology, Lymphoid Progenitor Cells physiology, Nuclear Proteins metabolism, Protein Biosynthesis physiology, Protein Inhibitors of Activated STAT metabolism, RNA-Binding Proteins metabolism, Ribosomal Proteins metabolism, Tumor Suppressor Protein p53 metabolism, V(D)J Recombination genetics
- Abstract
To be effective, the adaptive immune response requires a large repertoire of antigen receptors, which are generated through V(D)J recombination in lymphoid precursors. These precursors must be protected from DNA damage-induced cell death, however, because V(D)J recombination generates double-strand breaks and may activate p53. Here we show that the BTB/POZ domain protein Miz-1 restricts p53-dependent induction of apoptosis in both pro-B and DN3a pre-T cells that actively rearrange antigen receptor genes. Miz-1 exerts this function by directly activating the gene for ribosomal protein L22 (Rpl22), which binds to p53 mRNA and negatively regulates its translation. This mechanism limits p53 expression levels and thus contains its apoptosis-inducing functions in lymphocytes, precisely at differentiation stages in which V(D)J recombination occurs. more...
- Published
- 2014
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31. Inducible costimulator facilitates T-dependent B cell activation by augmenting IL-4 translation.
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Gigoux M, Lovato A, Leconte J, Leung J, Sonenberg N, and Suh WK
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, B-Lymphocytes cytology, B-Lymphocytes metabolism, Carrier Proteins immunology, Carrier Proteins metabolism, Cell Cycle Proteins, Cells, Cultured, Coculture Techniques, Eukaryotic Initiation Factors, Flow Cytometry, Germinal Center cytology, Germinal Center immunology, Germinal Center metabolism, Immunoblotting, Inducible T-Cell Co-Stimulator Protein genetics, Inducible T-Cell Co-Stimulator Protein metabolism, Interleukin-4 genetics, Interleukin-4 metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Phosphatidylinositol 3-Kinases immunology, Phosphatidylinositol 3-Kinases metabolism, Phosphoproteins immunology, Phosphoproteins metabolism, Phosphorylation immunology, Proto-Oncogene Proteins c-akt immunology, Proto-Oncogene Proteins c-akt metabolism, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, Reverse Transcriptase Polymerase Chain Reaction, Ribosomal Protein S6 Kinases, 70-kDa immunology, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Signal Transduction immunology, T-Lymphocytes, Helper-Inducer cytology, T-Lymphocytes, Helper-Inducer metabolism, TOR Serine-Threonine Kinases immunology, TOR Serine-Threonine Kinases metabolism, B-Lymphocytes immunology, Inducible T-Cell Co-Stimulator Protein immunology, Interleukin-4 immunology, Lymphocyte Activation immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
The inducible costimulator (ICOS) is highly expressed in follicular helper T (Tfh) cells, a subset of CD4 T cells that migrate into the B cell zone and facilitate germinal center reactions. Although ICOS is known to play a critical role in forming the Tfh cell population during immune responses, its contribution to the effector functions of Tfh cells remains unclear. Using activated mouse splenic CD4 T cells we demonstrate that ICOS assists TCR-mediated signal transduction by potentiating the PI3K-AKT-mTOR signaling cascade that leads to hyper-phosphorylation of p70S6K and 4E-BP1, events that are known to augment cap-dependent mRNA translation. Consequently, ICOS costimulation promotes the formation of polysomes on IL-4 mRNA in a PI3K-dependent manner. Furthermore, we show that the supply of IL-4 becomes a limiting factor for T-dependent B cell activation during in vitro co-culture when the ICOS-PI3K signaling axis is disrupted in T cells. This ICOS costimulation-dependent translational control may ensure targeted delivery of IL-4 to cognate B cells during T-B collaborations in the germinal center., (Copyright © 2014 Elsevier Ltd. All rights reserved.) more...
- Published
- 2014
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32. Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer.
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Lai AZ, Cory S, Zhao H, Gigoux M, Monast A, Guiot MC, Huang S, Tofigh A, Thompson C, Naujokas M, Marcus VA, Bertos N, Sehat B, Perera RM, Bell ES, Page BD, Gunning PT, Ferri LE, Hallett M, and Park M
- Subjects
- Cell Line, Tumor, Dual Specificity Phosphatase 6 genetics, Dual Specificity Phosphatase 6 metabolism, Dual-Specificity Phosphatases genetics, Dual-Specificity Phosphatases metabolism, HEK293 Cells, Humans, Mitogen-Activated Protein Kinase Phosphatases genetics, Mitogen-Activated Protein Kinase Phosphatases metabolism, Proto-Oncogene Proteins c-met genetics, Proto-Oncogene Proteins c-met metabolism, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Stomach Neoplasms genetics, Stomach Neoplasms pathology, Drug Resistance, Neoplasm, MAP Kinase Signaling System, Stomach Neoplasms metabolism
- Abstract
The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, initiated by a rapid decrease in the expression of genes encoding transcription factors, followed by those encoding proteins involved in epithelial-mesenchymal transition, and finally those encoding cell cycle-related proteins. In the gastric cancer cell lines, microarray and chromatin immunoprecipitation analysis revealed considerable overlap between genes regulated in response to Met stimulation and those regulated by signal transducer and activator of transcription 3 (STAT3). The activity of STAT3, extracellular signal-regulated kinase (ERK), and the kinase Akt was decreased by Met inhibition, but only inhibitors of STAT3 were as effective as the Met inhibitor in decreasing tumor cell proliferation in culture and in xenografts, suggesting that STAT3 mediates the pro-proliferative program induced by Met. However, the phosphorylation of ERK increased after prolonged Met inhibition in culture, correlating with decreased abundance of the phosphatases DUSP4 and DUSP6, which inhibit ERK. Combined inhibition of Met and the mitogen-activated protein kinase kinase (MEK)-ERK pathway induced greater cell death in cultured gastric cancer cells than did either inhibitor alone. These findings indicate combination therapies that may counteract resistance to Met inhibitors. more...
- Published
- 2014
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33. Phosphatidylinositol 3-kinase-independent signaling pathways contribute to ICOS-mediated T cell costimulation in acute graft-versus-host disease in mice.
- Author
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Li J, Heinrichs J, Leconte J, Haarberg K, Semple K, Liu C, Gigoux M, Kornete M, Piccirillo CA, Suh WK, and Yu XZ
- Subjects
- Acute Disease, Animals, Disease Models, Animal, Gene Knock-In Techniques, Graft vs Host Disease enzymology, Inducible T-Cell Co-Stimulator Protein deficiency, Lymphocyte Activation genetics, Mice, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Signal Transduction genetics, T-Lymphocyte Subsets enzymology, T-Lymphocyte Subsets metabolism, Graft vs Host Disease immunology, Graft vs Host Disease metabolism, Inducible T-Cell Co-Stimulator Protein physiology, Lymphocyte Activation immunology, Phosphatidylinositol 3-Kinase physiology, Signal Transduction immunology, T-Lymphocyte Subsets immunology
- Abstract
We and others have previously shown that ICOS plays an important role in inducing acute graft-versus-host disease (GVHD) in murine models of allogeneic bone marrow transplantation. ICOS potentiates TCR-mediated PI3K activation and intracellular calcium mobilization. However, ICOS signal transduction pathways involved in GVHD remain unknown. In this study, we examined the contribution of ICOS-PI3K signaling in the pathogenic potential of T cells using a knock-in mouse strain, ICOS-YF, which selectively lost the ability to activate PI3K. We found that when total T cells were used as alloreactive T cells, ICOS-YF T cells caused less severe GVHD compared with ICOS wild-type T cells, but they induced much more aggressive disease than ICOS knockout T cells. This intermediate level of pathogenic capacity of ICOS-YF T cells was correlated with similar levels of IFN-γ-producing CD8 T cells that developed in the recipients of ICOS-WT or ICOS-YF T cells. We further evaluated the role of ICOS-PI3K signaling in CD4 versus CD8 T cell compartment using GVHD models that are exclusively driven by CD4 or CD8 T cells. Remarkably, ICOS-YF CD8 T cells caused disease similar to ICOS wild-type CD8 T cells, whereas ICOS-YF CD4 T cells behaved very similarly to their ICOS knockout counterparts. Consistent with their in vivo pathogenic potential, CD8 T cells responded to ICOS ligation in vitro by PI3K-independent calcium flux, T cell activation, and proliferation. Thus, in acute GVHD in mice, CD4 T cells heavily rely on ICOS-PI3K signaling pathways; in contrast, CD8 T cells can use PI3K-independent ICOS signaling pathways, possibly through calcium. more...
- Published
- 2013
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34. Anti-chlamydial Th17 responses are controlled by the inducible costimulator partially through phosphoinositide 3-kinase signaling.
- Author
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Gao X, Gigoux M, Yang J, Leconte J, Yang X, and Suh WK
- Subjects
- Animals, Antibodies, Bacterial immunology, Antibody Formation genetics, Antibody Formation immunology, Bacterial Load, Chlamydia Infections microbiology, Disease Models, Animal, Female, Inducible T-Cell Co-Stimulator Protein genetics, Interferon-gamma biosynthesis, Lung immunology, Lung microbiology, Lung pathology, Mice, Spleen immunology, Spleen metabolism, Chlamydia Infections immunology, Chlamydia Infections metabolism, Chlamydia muridarum immunology, Inducible T-Cell Co-Stimulator Protein metabolism, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction, Th17 Cells immunology, Th17 Cells metabolism
- Abstract
We previously showed that mice deficient in the Inducible Costimulator ligand (ICOSL-KO) develop more severe disease and lung pathology with delayed bacterial clearance upon respiratory infection of Chlamydia muridarum. Importantly, the exacerbation of disease in ICOSL-KO mice was seen despite heightened IFN-γ/Th1 responses, the major defense mechanisms against Chlamydia. To gain insight into the mechanism of ICOS function in this model, we presently analyzed anti-Chlamydia immune responses in mice lacking the entire ICOS (ICOS-KO) versus knock-in mice expressing a mutant ICOS (ICOS-Y181F) that has selectively lost the ability to activate phosphoinositide 3-kinase (PI3K). Like ICOSL-KO mice, ICOS-KO mice showed worse disease with elevated IFN-γ/Th1 responses compared to wild-type (WT) mice. ICOS-Y181F mice developed much milder disease compared to ICOS-KO mice, yet they were still not fully protected to the WT level. This partial protection in ICOS-Y181F mice could not be explained by the magnitude of IFN-γ/Th1 responses since these mice developed a similar level of IFN-γ response compared to WT mice. It was rather IL-17/Th17 responses that reflected disease severity: IL-17/Th17 response was partially impaired in ICOS-Y181F mice compared to WT, but was substantially stronger than that of ICOS-KO mice. Consistently, we found that both polarization and expansion of Th17 cells were partially impaired in ICOS-Y181F CD4 T cells, and was further reduced in ICOS-KO CD4 T cells in vitro. Our results indicate that once the IFN-γ/Th1 response is above a threshold level, the IL-17/Th17 response becomes a limiting factor in controlling Chlamydia lung infection, and that ICOS plays an important role in promoting Th17 responses in part through the activation of PI3K. more...
- Published
- 2012
- Full Text
- View/download PDF
35. Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase.
- Author
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Gigoux M, Shang J, Pak Y, Xu M, Choe J, Mak TW, and Suh WK
- Subjects
- Animals, Antigens, Differentiation, T-Lymphocyte immunology, CD28 Antigens immunology, CD4-Positive T-Lymphocytes metabolism, Enzyme-Linked Immunosorbent Assay, Immunoprecipitation, Inducible T-Cell Co-Stimulator Protein, Interleukin-4 immunology, Interleukins immunology, Mice, Mice, Transgenic, Phosphatidylinositol 3-Kinases immunology, Interleukin-21, Antigens, Differentiation, T-Lymphocyte metabolism, CD28 Antigens metabolism, Cell Differentiation immunology, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
The T-cell costimulatory receptors, CD28 and the inducible costimulator (ICOS), are required for the generation of follicular B helper T cells (T(FH)) and germinal center (GC) reaction. A common signal transducer used by CD28 and ICOS is the phosphoinositide 3-kinase (PI3K). Although it is known that CD28-mediated PI3K activation is dispensable for GC reaction, the role of ICOS-driven PI3K signaling has not been defined. We show here that knock-in mice that selectively lost the ability to activate PI3K through ICOS had severe defects in T(FH) generation, GC reaction, antibody class switch, and antibody affinity maturation. In preactivated CD4(+) T cells, ICOS delivered a potent PI3K signal that was critical for the induction of the key T(FH) cytokines, IL-21 and IL-4. Under the same settings, CD28 was unable to activate PI3K but supported a robust secondary expansion of T cells. Thus, our results demonstrate a nonredundant function of ICOS-PI3K pathway in the generation of T(FH) and suggest that CD28 and ICOS play differential roles during a multistep process of T(FH) differentiation. more...
- Published
- 2009
- Full Text
- View/download PDF
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