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{"title"=>"Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression", "type"=>"journal", "authors"=>[{"first_name"=>"William L.", "last_name"=>"Redmond", "scopus_author_id"=>"7004217167"}, {"first_name"=>"Todd", "last_name"=>"Triplett", "scopus_author_id"=>"55171960400"}, {"first_name"=>"Kevin", "last_name"=>"Floyd", "scopus_author_id"=>"7007133601"}, {"first_name"=>"Andrew D.", "last_name"=>"Weinberg", "scopus_author_id"=>"7202001911"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84859354954", "scopus"=>"2-s2.0-84859354954", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"22496812", "pui"=>"364568868", "doi"=>"10.1371/journal.pone.0034467"}, "id"=>"232a4ad8-2073-3b0e-864f-a7526343dc16", "abstract"=>"The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy.", "link"=>"http://www.mendeley.com/research/dual-antiox40il2-therapy-augments-tumor-immunotherapy-via-il2rmediated-regulation-ox40-expression", "reader_count"=>19, "reader_count_by_academic_status"=>{"Researcher"=>7, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>1, "Other"=>2, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>7, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>1, "Other"=>2, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>8, "Medicine and Dentistry"=>5, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}}, "reader_count_by_country"=>{"Netherlands"=>1, "France"=>1}, "group_count"=>3}

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• http://doi.org/10.1158/1078-0432.CCR-12-2065
• http://doi.org/10.1186/s40425-014-0028-y
• http://doi.org/10.1158/2326-6066.CIR-18-0222
• http://doi.org/10.1158/0008-5472.CAN-12-3343
• http://doi.org/10.1155/2014/789069
• http://doi.org/10.1158/1078-0432.CCR-12-2214
• http://doi.org/10.1093/imammb/dqw021
• http://doi.org/10.4049/jimmunol.1901052
• http://doi.org/10.1186/2051-1426-2-7
• http://doi.org/10.4110/in.2020.20.e3
• http://doi.org/10.1080/2162402X.2015.1052212
• http://doi.org/10.1016/j.apsb.2019.08.010
• http://doi.org/10.1016/j.it.2015.10.003
• http://doi.org/10.1080/21645515.2016.1193277
• http://doi.org/10.1016/j.transproceed.2013.03.038
• http://doi.org/10.1038/s41419-018-0659-x
• http://doi.org/10.1093/infdis/jiz237
• http://doi.org/10.1158/2326-6066.CIR-14-0174
• http://doi.org/10.3389/fonc.2015.00034
• http://doi.org/10.1158/2326-6066.CIR-20-0338
• http://doi.org/10.1517/14712598.2014.890586
• http://doi.org/10.3892/ijmm.2016.2808
• http://doi.org/10.1155/2013/371854
• http://doi.org/10.1053/j.seminoncol.2015.05.014
• http://doi.org/10.1111/imr.12644
• http://doi.org/10.1158/2326-6066.CIR-13-0031-T

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Figshare

• {"files"=>["https://ndownloader.figshare.com/files/658574"], "description"=>"<p>Wild-type mice received 1×10⁶ MCA-205 sarcoma tumor cells (n = 2–3/group). Tumor-bearing mice were treated with anti-OX40 or rat IgG Ab (days 10, 14; i.p.) along with IL-2 cytokine/mAb complexes (days 10–13; i.p.). On day 21, Treg were isolated from the spleens of tumor-bearing hosts and co-cultured with naïve CFSE-labeled responder CD8 T cells. Cells were harvested 96 hours later and the extent of CFSE dilution and in the CD8 responder cells was determined by flow cytometry. Graphs depict the results from A) individual mice or B) the mean+/−SD from n = 2–3/group.</p>", "links"=>[], "tags"=>["immunology", "molecular biology"], "article_id"=>329067, "categories"=>["Molecular Biology", "Immunology"], "users"=>["William L. Redmond", "Todd Triplett", "Kevin Floyd", "Andrew D. Weinberg"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034467.g007", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Treg_functional_assay_/329067", "title"=>"Treg functional assay.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-04 02:31:07"}
• {"files"=>["https://ndownloader.figshare.com/files/658037"], "description"=>"<p><b>A</b>) Naïve WT OT-I T cells were stimulated with peptide-pulsed APCs (as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034467#pone-0034467-g003\" target=\"_blank\">Fig. 3A</a>). <b>A</b>) Two days later, OT-I T cells were harvested and re-cultured (5×10⁵ cells/ml) with media or rmIL-2 (100 ng/ml) and the expression of the indicated proteins was assessed by Western blot. <b>B</b>) WT OT-I T cells were stimulated (as in (<b>A</b>)) +/− a JAK3 inhibitor (PF-956980; 100 ng/ml). Twenty-four hours later, cells were harvested and the extent of CD25 and OX40 expression was determined. <b>C, D</b>) WT or OX40^−/− OT-I cells were stimulated for 2 days, harvested, and then re-stimulated with media alone, rmIL-2, rmIL-4, rmIL-7, rmIL-9, rmIL-15, or rmIL-21 (100 ng/ml). Twenty-four hours later, cells were harvested and the extent of <b>C</b>) CD25 and <b>D</b>) OX40 expression (% positive and MFI) were determined. <b>E</b>) WT OT-I T cells were activated and then re-stimulated with the indicated common gc cytokines and protein expression was assessed by Western blot. <b>B–D</b>) Bar graphs depict the mean+/−SD from <b>B</b>) n = 2–3/group or <b>C, D</b>) n = 3–8/group. Data are representative of one out of two to ten independent experiments. *P<0.05; ** P<0.01; *** P<0.001.</p>", "links"=>[], "tags"=>["gc", "cytokines", "ox40"], "article_id"=>328523, "categories"=>["Molecular Biology", "Immunology"], "users"=>["William L. Redmond", "Todd Triplett", "Kevin Floyd", "Andrew D. Weinberg"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034467.g003", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Common_gc_cytokines_regulate_OX40_via_JAK_STAT_signaling_/328523", "title"=>"Common gc cytokines regulate OX40 via JAK/STAT signaling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-04 02:22:03"}
• {"files"=>["https://ndownloader.figshare.com/files/658741"], "description"=>"<p><b>A</b>) Tumor model. 2.5×10⁶ TRAMP-C1-mOVA tumor cells were injected into POET-1 mice. Twenty days later, mice (∼50 mm² tumors) received 5×10⁵ naïve OT-I T cells. Seventeen days after T cell adoptive transfer (37 days post-tumor inoculation), the anergic donor OT-I T cells were re-stimulated with anti-OX40 or control (rat IgG) Ab (d37-38), 500 mcg OVA (d37), 10 mcg LPS (d37), +/− IL-2 cytokine/mAb complexes (d37-44). <b>B</b>) Seven days after the initial dose of Ag/anti-OX40 the extent of donor CD8 T cell expansion (% OT-I of total CD8 T cells; pre- vs. post-treatment), Ki-67 (proliferation), granzyme B, and KLRG-1 expression on the donor OT-I T cells were determined. <b>C</b>) Tumor-bearing mice were treated as in (<b>B</b>) and then seven days later OVA peptide-pulsed (CFSE^high) and control HA peptide-pulsed (CFSE^low) target cells were mixed at a 1∶1 ratio and injected into recipient mice. Four hours later, spleens were harvested and the ratio of % CFSE^low/% CFSE^high target cells from individual mice (n = 5/group) was determined. <b>D, E</b>) The extent of tumor growth (mean+/−SD; n = 5/group) and <b>D</b>) survival (n = 11/group) of tumor-bearing mice were assessed. Data are representative of one out of 2 to 3 independent experiments or <b>E</b>) the cumulative survival from 2 independent experiments. *P<0.05, **P<0.01.</p>", "links"=>[], "tags"=>["reverses", "cd8", "anergy", "increases", "mice", "well-established"], "article_id"=>329230, "categories"=>["Molecular Biology", "Immunology"], "users"=>["William L. Redmond", "Todd Triplett", "Kevin Floyd", "Andrew D. Weinberg"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034467.g008", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dual_anti_OX40_IL_2c_therapy_reverses_CD8_T_cell_anergy_and_increases_the_survival_of_mice_with_long_term_well_established_tumors_/329230", "title"=>"Dual anti-OX40/IL-2c therapy reverses CD8 T cell anergy and increases the survival of mice with long-term well-established tumors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-04 02:33:50"}
• {"files"=>["https://ndownloader.figshare.com/files/658296"], "description"=>"<p><b>A, B</b>) C57BL/6 OX40-cre x ROSA-YFP reporter mice received 1×10⁶ MCA-205 sarcoma tumor cells (day 0) and two weeks later, the tumor-bearing mice were treated with IL-2 cytokine/mAb complexes (day 14, 15; i.p.). Twenty four hours later (day 16 post-tumor inoculation) the extent of CD25, YFP (OX40 reporter), and OX40 expression on CD8 T cells isolated from the <b>A</b>) tumor and <b>B</b>) spleen were assessed. Graphs depict the results obtained from 3–4 individual animals from 1 out of 2 independent experiments.</p>", "links"=>[], "tags"=>["enhanced", "ox40", "cd8", "cells", "tumor-bearing"], "article_id"=>328779, "categories"=>["Molecular Biology", "Immunology"], "users"=>["William L. Redmond", "Todd Triplett", "Kevin Floyd", "Andrew D. Weinberg"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034467.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IL_2_treatment_enhanced_OX40_expression_on_CD8_T_cells_in_tumor_bearing_hosts_/328779", "title"=>"IL-2 treatment enhanced OX40 expression on CD8 T cells in tumor-bearing hosts.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-04 02:26:19"}
• {"files"=>["https://ndownloader.figshare.com/files/658431"], "description"=>"<p><b>A, B</b>) Wild-type mice received 1×10⁶ MCA-205 sarcoma tumor cells (n = 8/group). Tumor-bearing mice were treated with anti-OX40 or rat IgG Ab (days 10, 14; i.p.) along with IL-2 cytokine/mAb complexes (days 10–13; i.p.) and the extent of <b>A</b>) tumor growth and <b>B</b>) survival of tumor-bearing mice were assessed. Data are representative of one out of 2 independent experiments. <b>C</b>) MCA-205 tumor-bearing mice (as in (<b>A</b>)) received no treatment (n = 9), anti-CD4 (n = 6), anti-CD8 (n = 6), or anti-CD4+anti-CD8 (n = 3) (200 mcg/dose; i.p.) 9, 17, and 24 days post-tumor implantation. Mice were then treated with anti-OX40 (days 10, 14) and IL-2c (days 10–13) and the extent of survival of tumor-bearing mice was assessed.</p>", "links"=>[], "tags"=>["boosts", "anti-tumor", "immunity", "cell-dependent"], "article_id"=>328916, "categories"=>["Molecular Biology", "Immunology"], "users"=>["William L. Redmond", "Todd Triplett", "Kevin Floyd", "Andrew D. Weinberg"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034467.g006", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combined_anti_OX40_IL_2c_therapy_boosts_anti_tumor_immunity_through_a_T_cell_dependent_mechanism_/328916", "title"=>"Combined anti-OX40/IL-2c therapy boosts anti-tumor immunity through a T cell-dependent mechanism.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-04 02:28:36"}
• {"files"=>["https://ndownloader.figshare.com/files/338152", "https://ndownloader.figshare.com/files/338183"], "description"=>"<div><p>The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy.</p> </div>", "links"=>[], "tags"=>["dual", "augments", "immunotherapy", "il-2r-mediated", "ox40"], "article_id"=>126837, "categories"=>["Molecular Biology", "Immunology"], "users"=>["William L. Redmond", "Todd Triplett", "Kevin Floyd", "Andrew D. Weinberg"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0034467.s001", "https://dx.doi.org/10.1371/journal.pone.0034467.s002"], "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Dual_Anti_OX40_IL_2_Therapy_Augments_Tumor_Immunotherapy_via_IL_2R_Mediated_Regulation_of_OX40_Expression/126837", "title"=>"Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-04-04 01:53:57"}
• {"files"=>["https://ndownloader.figshare.com/files/657892"], "description"=>"<p><b>A</b>) Purified naïve wild-type or OX40^−/− OT-I T cells (1×10⁶/ml) were stimulated with peptide-pulsed APCs (6×10⁶/ml). Two days later, OT-I T cells were harvested and re-cultured (5×10⁵ cells/ml) +/− rmIL-2 (100 ng/ml). Twenty-four hours later, cells were harvested and the extent of CD25 and OX40 expression were determined. Bar graphs depict the mean+/−SEM (n = 6/group). <b>B, C</b>) Human CD8 or <b>C</b>) CD4 T cells collected from PBMC were stimulated with media, rhIL-2 (5,000 IU/ml, equivalent to 300 ng/ml), and/or 1 mcg/ml anti-CD3 mAb (OKT-3). Forty-eight hours later, cells were harvested, washed, and stimulated with media or rhIL-2 (5,000 IU/ml). Twenty-four hours later, the extent of CD25 and OX40 expression were measured. <b>C</b>) Bar graphs depict the mean+/−SD (n = 3–5/group). Data are pooled from five independent experiments. *P<0.05; **P<0.01; ***P<0.001.</p>", "links"=>[], "tags"=>["regulated", "murine", "cells", "tcr", "stimulation"], "article_id"=>328374, "categories"=>["Molecular Biology", "Immunology"], "users"=>["William L. Redmond", "Todd Triplett", "Kevin Floyd", "Andrew D. Weinberg"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034467.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_OX40_is_regulated_on_murine_and_human_T_cells_by_TCR_stimulation_and_IL_2_/328374", "title"=>"OX40 is regulated on murine and human T cells by TCR stimulation and IL-2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-04 02:19:34"}
• {"files"=>["https://ndownloader.figshare.com/files/658185"], "description"=>"<p><b>A</b>) WT or STAT3^−/− OT-I T cells were stimulated for 2 days, harvested, and then re-cultured with media alone, rmIL-2, rmIL-4, or rmIL-21 (100 ng/ml); 24 hours later cells were harvested and the extent of CD25 and OX40 expression (% positive and MFI) were measured. <b>B</b>) Polyclonal endogenous WT or STAT5^−/− CD8 T cells were stimulated for 2 days with 2 mcg/ml anti-CD3 mAb, harvested, and then re-cultured with media alone, rmIL-2, rmIL-4, or rmIL-21 (100 ng/ml) and then 24 hours later, cells were harvested and the extent of CD25 and OX40 expression (% positive and MFI) were determined. <b>A, B</b>) Bar graphs depict the mean+/−SD (n = 2–3/group). Data are representative of one out of two independent experiments. *P<0.05; ** P<0.01; *** P<0.001; NS = no statistically significant difference.</p>", "links"=>[], "tags"=>["stat5", "optimal", "up-regulation", "ox40", "stimulation", "gc"], "article_id"=>328666, "categories"=>["Molecular Biology", "Immunology"], "users"=>["William L. Redmond", "Todd Triplett", "Kevin Floyd", "Andrew D. Weinberg"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034467.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_STAT3_and_STAT5_are_required_for_optimal_up_regulation_of_OX40_following_stimulation_with_common_gc_cytokines_/328666", "title"=>"STAT3 and STAT5 are required for optimal up-regulation of OX40 following stimulation with common gc cytokines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-04 02:24:26"}
• {"files"=>["https://ndownloader.figshare.com/files/657700"], "description"=>"<p>(<b>A, B</b>) Naïve wild-type or OX40^−/− OT-I T cells (2×10⁵/ml) were stimulated with peptide-pulsed APCs (2×10³/ml). <b>A</b>) Three days later, OT-I T cells were harvested and the extent of CD25 and OX40 expression were determined. <b>B</b>) Kinetics of CD25 and OX40 expression following TCR stimulation were determined at the indicated time points by flow cytometry. (<b>C</b>) Naïve polyclonal wild-type or CD25^−/− CD8 T cells (3×10⁵/well) were CFSE-labeled and then stimulated with anti-CD3 and anti-CD28 (1 and 5 mcg/ml, respectively). One to three days later, CD8 T cells were harvested and the extent of CD25 and OX40 expression were determined. <b>B, C</b>) Bar graphs depict the mean+/−SD (n = 2–3/group). Data are representative of one out of two to three independent experiments. *P<0.05.</p>", "links"=>[], "tags"=>["regulated", "tcr", "stimulation", "il-2ralpha"], "article_id"=>328187, "categories"=>["Molecular Biology", "Immunology"], "users"=>["William L. Redmond", "Todd Triplett", "Kevin Floyd", "Andrew D. Weinberg"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034467.g001", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_OX40_is_regulated_by_TCR_stimulation_and_IL_2Ralpha_CD25_expression_/328187", "title"=>"OX40 is regulated by TCR stimulation and IL-2Ralpha (CD25) expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-04 02:16:27"}

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Relative Metric

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F1000Prime