Blockade of PD-1/PD-L1 Promotes Adoptive T-Cell Immunotherapy in a Tolerogenic Environment
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{"title"=>"Blockade of PD-1/PD-L1 promotes adoptive T-Cell immunotherapy in a tolerogenic environment", "type"=>"journal", "authors"=>[{"first_name"=>"Stephen J.P.", "last_name"=>"Blake", "scopus_author_id"=>"23988512600"}, {"first_name"=>"Alan L.H.", "last_name"=>"Ching", "scopus_author_id"=>"56538089800"}, {"first_name"=>"Tony J.", "last_name"=>"Kenna", "scopus_author_id"=>"6602781126"}, {"first_name"=>"Ryan", "last_name"=>"Galea", "scopus_author_id"=>"57196587570"}, {"first_name"=>"Justin", "last_name"=>"Large", "scopus_author_id"=>"56538104500"}, {"first_name"=>"Hideo", "last_name"=>"Yagita", "scopus_author_id"=>"55192275000"}, {"first_name"=>"Raymond J.", "last_name"=>"Steptoe", "scopus_author_id"=>"6701551792"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84924090823", "doi"=>"10.1371/journal.pone.0119483", "pui"=>"602685038", "pmid"=>"25741704", "scopus"=>"2-s2.0-84924090823", "issn"=>"19326203"}, "id"=>"ec408818-13d8-3939-9a5a-620d24e74050", "abstract"=>"Adoptive cellular immunotherapy using in vitro expanded CD8+ T cells shows promise for tumour immunotherapy but is limited by eventual loss of function of the transferred T cells through factors that likely include inactivation by tolerogenic dendritic cells (DC). The co-inhibitory receptor programmed death-1 (PD-1), in addition to controlling T-cell responsiveness at effector sites in malignancies and chronic viral diseases is an important modulator of dendritic cell-induced tolerance in naive T cell populations. The most potent therapeutic capacity amongst CD8+ T cells appears to lie within Tcm or Tcm-like cells but memory T cells express elevated levels of PD-1. Based on established trafficking patterns for Tcm it is likely Tcm-like cells interact with lymphoid-tissue DC that present tumour-derived antigens and may be inherently tolerogenic to develop therapeutic effector function. As little is understood of the effect of PD-1/PD-L1 blockade on Tcm-like CD8+ T cells, particularly in relation to inactivation by DC, we explored the effects of PD-1/PD-L1 blockade in a mouse model where resting DC tolerise effector and memory CD8+ T cells. Blockade of PD-1/PD-L1 promoted effector differentiation of adoptively-transferred Tcm-phenotype cells interacting with tolerising DC. In tumour-bearing mice with tolerising DC, effector activity was increased in both lymphoid tissues and the tumour-site and anti-tumour activity was promoted. Our findings suggest PD-1/PD-L1 blockade may be a useful adjunct for adoptive immunotherapy by promoting effector differentiation in the host of transferred Tcm-like cells.", "link"=>"http://www.mendeley.com/research/blockade-pd1pdl1-promotes-adoptive-tcell-immunotherapy-tolerogenic-environment", "reader_count"=>50, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Student > Doctoral Student"=>4, "Researcher"=>12, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>3, "Student > Master"=>7, "Other"=>2, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Student > Doctoral Student"=>4, "Researcher"=>12, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>3, "Student > Master"=>7, "Other"=>2, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>17, "Medicine and Dentistry"=>10, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Chemistry"=>1, "Immunology and Microbiology"=>9}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>10}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>9}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>17}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"United States"=>1, "Japan"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1941430"], "description"=>"<p>A) CD45.1<sup>+</sup> OT-I T cells were transferred to 11c.OVA or C57BL/6 (non-Tg) mice treated with αPD-1, αPD-L1 or isotype control mAb at transfer and every subsequent three days. At the indicated time points after transfer spleens were collected and OT-I T cell number determined by a flow-cytometric counting assay. B-E): CD45.1<sup>+</sup> OT-I T cells were transferred to C57BL/6 (non-Tg) or 11c.OVA mice and 21 days later mice were treated with αPD-1, αPD-L1 or isotype control mAb every three days. Six days after commencement of mAb treatment some mice were challenged with OVA/QuilA immunization and a further five days later mice were euthanized and tissues collected for analysis using a flow-cytometric counting assay and intracellular cytokine staining. (A) ***: for 11c.OVA recipients, αPD-L1 significantly greater than isotype control at day 3, 7, 14 (p<0.001), αPD-L1 significantly greater than αPD-1 at d7 (p<0.001) and d14 (p<0.05), αPD-1 greater than isotype at day 3 (p<0.001) and day 7, 14 (p<0.05). Data comprise: (A) four to seven mice for each time point (mean ± SEM) pooled from two or more experiments with 2–3 mice per group, (B-E) data pooled from 2 or 3 individual experiments with 1–2 mice per group (n = 4 for all groups) with values for individual mice shown.</p>", "links"=>[], "tags"=>["DC tolerise effector", "tolerising DC", "pd", "effector differentiation", "Tolerogenic Environment Adoptive", "T cell populations", "Memory T cells", "tolerogenic dendritic cells"], "article_id"=>1329731, "categories"=>["Biological Sciences"], "users"=>["Stephen J. P. Blake", "Alan L. H. Ching", "Tony J. Kenna", "Ryan Galea", "Justin Large", "Hideo Yagita", "Raymond J. Steptoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0119483.g001", "stats"=>{"downloads"=>1, "page_views"=>25, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Blockade_of_PD_1_PD_L1_impairs_induction_and_partially_reverses_tolerance_in_na_ve_CD8_T_cells_/1329731", "title"=>"Blockade of PD-1/PD-L1 impairs induction and partially reverses tolerance in naïve CD8<sup>+</sup> T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-05 10:35:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/1941431"], "description"=>"<p>A, B) In vitro generated CD45.1<sup>+</sup> OT-I memory T cells were transferred to 11c.OVA or C57BL/6 (non-Tg) mice treated with αPD-1, αPD-L1 or isotype control mAb at transfer and every subsequent three days. At the indicated time points spleens were collected and OT-I T cell number (A) and total IFN-γ-producing OT-I number (B) determined by a flow-cytometric counting assay and intracellular cytokine staining. C, D) In vitro generated CD45.1<sup>+</sup> OT-I Tcm-phenotype cells were transferred to 11c.OVA or C57BL/6 (non-Tg) mice treated with αPD-1, αPD-L1 or isotype control mAb at transfer and every subsequent 3 days and seven (C) or 14 (D) days later CTL activity determined in vivo. Data comprise: (A) 4–6 mice for each time point (mean ± SEM) pooled from two or more experiments of 2–3 mice per group, ** 11c.OVA + αPD-L1 significantly greater than 11c.OVA + isotype and 11c.OVA + αPD-1 at day 7 (p<0.01), (B) 4–6 mice for each time point (mean ± SEM) pooled from more than two experiments of 2 mice per group, * 11c.OVA + αPD-L1 significantly greater than 11c.OVA + isotype and 11c.OVA + αPD-1 at day 3 (p<0.05), ** 11c.OVA + αPD-L1 significantly greater than 11c.OVA + isotype and 11c.OVA + αPD-1 at day 7 (p<0.01), (C, D) data pooled from 2 individual experiments of 2 mice per group with values for individual mice shown.</p>", "links"=>[], "tags"=>["DC tolerise effector", "tolerising DC", "pd", "effector differentiation", "Tolerogenic Environment Adoptive", "T cell populations", "Memory T cells", "tolerogenic dendritic cells"], "article_id"=>1329732, "categories"=>["Biological Sciences"], "users"=>["Stephen J. P. Blake", "Alan L. H. Ching", "Tony J. Kenna", "Ryan Galea", "Justin Large", "Hideo Yagita", "Raymond J. Steptoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0119483.g002", "stats"=>{"downloads"=>0, "page_views"=>41, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Blockade_of_PD_1_PD_L1_impairs_tolerance_in_memory_CD8_T_cells_/1329732", "title"=>"Blockade of PD-1/PD-L1 impairs tolerance in memory CD8<sup>+</sup> T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-05 10:35:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/1941433"], "description"=>"<p>A, B) In vitro generated memory CD45.1<sup>+</sup> OT-I T cells were transferred to 11c.OVA or C57BL/6 mice. Twenty eight days later mice were treated with αPD-1, αPD-L1 or isotype control mAb every subsequent three days. Nine days after commencement of mAb treatment some mice were challenged with OVA/QuilA immunization and a further five days later mice were euthanized and tissues collected for analysis using a flow-cytometric counting assay and intracellular cytokine staining. Data comprise: (A) four mice pooled from 4 experiments with n = 1 for each treatment set. Values for individual mice shown.</p>", "links"=>[], "tags"=>["DC tolerise effector", "tolerising DC", "pd", "effector differentiation", "Tolerogenic Environment Adoptive", "T cell populations", "Memory T cells", "tolerogenic dendritic cells"], "article_id"=>1329734, "categories"=>["Biological Sciences"], "users"=>["Stephen J. P. Blake", "Alan L. H. Ching", "Tony J. Kenna", "Ryan Galea", "Justin Large", "Hideo Yagita", "Raymond J. Steptoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0119483.g003", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Blockade_of_PD_1_PD_L1_partially_reverses_non_responsiveness_of_tolerised_memory_CD8_T_cells_/1329734", "title"=>"Blockade of PD-1/PD-L1 partially reverses non-responsiveness of tolerised memory CD8<sup>+</sup> T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-05 10:35:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/1941434"], "description"=>"<p>A) B16.mOVA cells were analysed for expression of PD-1 and PD-1 ligands. Histogram plots show specific antibody (solid line) and isotype control (dashed line) stained cells. Data are from a single analysis representative of 3 separate analyses. B) B16.mOVA cells (10<sup>5</sup>) were injected s.c. to 11c.OVA mice. Mice were left untreated (●) or 3 days later OT-I Tcm-phenotype cells (5 x 10<sup>6</sup>) transferred i.v. OT-I recipients were injected on the day of OT-I transfer and every subsequent 3 days with isotype control (◯), αPD-1 (▲) or αPD-L1 (▽) mAb. C-E) B16.mOVA cells (10<sup>5</sup>, C; 0.5 x 10<sup>5</sup>, D; 0.25 x 10<sup>5</sup>, E) were injected s.c. to C57BL/6 (C) or 11c.OVA mice (D, E). Mice were left untreated (●) or 3 days later OT-I Tcm-phenotype cells (5 x 10<sup>6</sup>) transferred i.v. OT-I recipients were injected on the day of OT-I transfer and every subsequent 3 days with isotype control (◯), αPD-1 (▲) or αPD-L1 (▽) mAb. Data show survival curves (left) or cumulative mean tumour area ± SEM (right).</p>", "links"=>[], "tags"=>["DC tolerise effector", "tolerising DC", "pd", "effector differentiation", "Tolerogenic Environment Adoptive", "T cell populations", "Memory T cells", "tolerogenic dendritic cells"], "article_id"=>1329735, "categories"=>["Biological Sciences"], "users"=>["Stephen J. P. Blake", "Alan L. H. Ching", "Tony J. Kenna", "Ryan Galea", "Justin Large", "Hideo Yagita", "Raymond J. Steptoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0119483.g004", "stats"=>{"downloads"=>5, "page_views"=>73, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Anti_PD_1_and_anti_PD_L1_synergises_with_Tcm_phenotype_cell_transfer_to_a_tolerogenic_environment_/1329735", "title"=>"Anti-PD-1 and anti-PD-L1 synergises with Tcm-phenotype cell transfer to a tolerogenic environment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-05 10:35:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/1941435"], "description"=>"<p>A-G) B16.mOVA cells (10<sup>5</sup>) were injected s.c. to 11c.OVA mice and 3 days later OT-I Tcm-phenotype cells (5 x 10<sup>6</sup>) transferred i.v. OT-I recipients were injected on the day of OT-I transfer and every subsequent 3 days with isotype control or αPD-L1 mAb as indicated. Twelve days after OT-I Tcm-phenotype cell transfer, spleen (A, E), tumour draining LN (TDLN) (B), and tumour (C, D, F, G) were harvested and OT-I (CD45.1<sup>+</sup>/CD8<sup>+</sup>/Vα2<sup>+</sup>) number and cytokine production determined using a flow-cytometric counting assay (A, B, C, D) and intracellular cytokine staining (E, F) or a combination of both. Data represent individual mice pooled from 2 experiments of 2–3 mice per group.</p>", "links"=>[], "tags"=>["DC tolerise effector", "tolerising DC", "pd", "effector differentiation", "Tolerogenic Environment Adoptive", "T cell populations", "Memory T cells", "tolerogenic dendritic cells"], "article_id"=>1329736, "categories"=>["Biological Sciences"], "users"=>["Stephen J. P. Blake", "Alan L. H. Ching", "Tony J. Kenna", "Ryan Galea", "Justin Large", "Hideo Yagita", "Raymond J. Steptoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0119483.g005", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Anti_PD_L1_treatment_increases_tumour_specific_CD8_T_cell_infiltration_and_promotes_effector_function_within_tumours_/1329736", "title"=>"Anti-PD-L1 treatment increases tumour-specific CD8<sup>+</sup> T cell infiltration and promotes effector function within tumours.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-05 10:35:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/1941437"], "description"=>"<p>A-G) B16.mOVA cells (10<sup>5</sup>) were injected s.c. to 11c.OVA mice and 3 days later OT-I Tcm-phenotype cells (5 x 10<sup>6</sup>) transferred i.v. OT-I recipients were injected on the day of OT-I transfer and every subsequent 3 days with isotype control or αPD-L1 mAb as indicated. Twelve days after OT-I Tcm-phenotype cells transfer, spleen, tumour draining LN (TDLN), and tumour sites were harvested for flow-cytometric analysis. A) PD-L1 expression was determined in tumour, spleen and TDLN (A) gated on the total bulk population for isotype control mAb-injected (solid line) mice. Isotype-control staining of tumour is shown (dashed line). B, C) the proportion of DC expressing PD-L1 (B) and PD-L1 expression level on DC (C) was determined (gated on CD11c<sup>+</sup>I-A<sup>b+</sup> DC). CD62L and CD44 (D), PD-1 (E, F) and LAG-3 (G) expression was determined on OT-I T cells in spleen, TDLN and tumour. Data are representative of 3 mice/group in 2 separate experiments (A) or individual mice pooled from 2 separate experiments of 2–3 mice per group (B-G) except TDLN in (B, C) which is 3 mice from a single experiment of the 2 performed.</p>", "links"=>[], "tags"=>["DC tolerise effector", "tolerising DC", "pd", "effector differentiation", "Tolerogenic Environment Adoptive", "T cell populations", "Memory T cells", "tolerogenic dendritic cells"], "article_id"=>1329738, "categories"=>["Biological Sciences"], "users"=>["Stephen J. P. Blake", "Alan L. H. Ching", "Tony J. Kenna", "Ryan Galea", "Justin Large", "Hideo Yagita", "Raymond J. Steptoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0119483.g006", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Anti_PD_L1_treatment_reduces_exhaustion_marker_expression_on_tumour_specific_CD8_T_cells_/1329738", "title"=>"Anti-PD-L1 treatment reduces exhaustion marker expression on tumour-specific CD8<sup>+</sup> T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-05 10:35:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/1941438", "https://ndownloader.figshare.com/files/1941439", "https://ndownloader.figshare.com/files/1941440", "https://ndownloader.figshare.com/files/1941441"], "description"=>"<div><p>Adoptive cellular immunotherapy using in vitro expanded CD8<sup>+</sup> T cells shows promise for tumour immunotherapy but is limited by eventual loss of function of the transferred T cells through factors that likely include inactivation by tolerogenic dendritic cells (DC). The co-inhibitory receptor programmed death-1 (PD-1), in addition to controlling T-cell responsiveness at effector sites in malignancies and chronic viral diseases is an important modulator of dendritic cell-induced tolerance in naive T cell populations. The most potent therapeutic capacity amongst CD8<sup>+</sup> T cells appears to lie within Tcm or Tcm-like cells but memory T cells express elevated levels of PD-1. Based on established trafficking patterns for Tcm it is likely Tcm-like cells interact with lymphoid-tissue DC that present tumour-derived antigens and may be inherently tolerogenic to develop therapeutic effector function. As little is understood of the effect of PD-1/PD-L1 blockade on Tcm-like CD8<sup>+</sup> T cells, particularly in relation to inactivation by DC, we explored the effects of PD-1/PD-L1 blockade in a mouse model where resting DC tolerise effector and memory CD8<sup>+</sup> T cells. Blockade of PD-1/PD-L1 promoted effector differentiation of adoptively-transferred Tcm-phenotype cells interacting with tolerising DC. In tumour-bearing mice with tolerising DC, effector activity was increased in both lymphoid tissues and the tumour-site and anti-tumour activity was promoted. Our findings suggest PD-1/PD-L1 blockade may be a useful adjunct for adoptive immunotherapy by promoting effector differentiation in the host of transferred Tcm-like cells.</p></div>", "links"=>[], "tags"=>["DC tolerise effector", "tolerising DC", "pd", "effector differentiation", "Tolerogenic Environment Adoptive", "T cell populations", "Memory T cells", "tolerogenic dendritic cells"], "article_id"=>1329739, "categories"=>["Biological Sciences"], "users"=>["Stephen J. P. Blake", "Alan L. H. Ching", "Tony J. Kenna", "Ryan Galea", "Justin Large", "Hideo Yagita", "Raymond J. Steptoe"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0119483.s001", "https://dx.doi.org/10.1371/journal.pone.0119483.s002", "https://dx.doi.org/10.1371/journal.pone.0119483.s003", "https://dx.doi.org/10.1371/journal.pone.0119483.s004"], "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Blockade_of_PD_1_PD_L1_Promotes_Adoptive_T_Cell_Immunotherapy_in_a_Tolerogenic_Environment_/1329739", "title"=>"Blockade of PD-1/PD-L1 Promotes Adoptive T-Cell Immunotherapy in a Tolerogenic Environment", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-03-05 10:35:42"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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