Cell-Extrinsic Effects of Tumor ER Stress Imprint Myeloid Dendritic Cells and Impair CD8+ T Cell Priming
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{"title"=>"Cell-Extrinsic Effects of Tumor ER Stress Imprint Myeloid Dendritic Cells and Impair CD8+ T Cell Priming", "type"=>"journal", "authors"=>[{"first_name"=>"Navin R.", "last_name"=>"Mahadevan", "scopus_author_id"=>"8053216000"}, {"first_name"=>"Veronika", "last_name"=>"Anufreichik", "scopus_author_id"=>"55532532800"}, {"first_name"=>"Jeffrey J.", "last_name"=>"Rodvold", "scopus_author_id"=>"36521570700"}, {"first_name"=>"Kevin T.", "last_name"=>"Chiu", "scopus_author_id"=>"55514979900"}, {"first_name"=>"Homero", "last_name"=>"Sepulveda", "scopus_author_id"=>"36788726500"}, {"first_name"=>"Maurizio", "last_name"=>"Zanetti", "scopus_author_id"=>"7102283250"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84871265006", "pmid"=>"23272178", "sgr"=>"84871265006", "doi"=>"10.1371/journal.pone.0051845", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203", "pui"=>"366299106"}, "id"=>"0bf6b09b-d5e2-3b59-a385-1d27932895b6", "abstract"=>"Tumor-infiltrating myeloid cells, such as dendritic cells (BMDC), are key regulators of tumor growth. However, the tumor-derived signals polarizing BMDC to a phenotype that subverts cell-mediated anti-tumor immunity have yet to be fully elucidated. Addressing this unresolved problem we show that the tumor unfolded protein response (UPR) can function in a cell-extrinsic manner via the transmission of ER stress (TERS) to BMDC. TERS-imprinted BMDC upregulate the production of pro-inflammatory, tumorigenic cytokines but also the immunosuppressive enzyme arginase. Importantly, they downregulate cross-presentation of high-affinity antigen and fail to effectively cross-prime CD8(+) T cells, causing T cell activation without proliferation and similarly dominantly suppress cross-priming by bystander BMDC. Lastly, TERS-imprinted BMDC facilitate tumor growth in vivo with fewer tumor-infiltrating CD8(+) T cells. In sum, we demonstrate that tumor-borne ER stress imprints ab initio BMDC to a phenotype that recapitulates several of the inflammatory/suppressive characteristics ascribed to tumor-infiltrating myeloid cells, highlighting the tumor UPR as a critical controller of anti-tumor immunity and a new target for immune modulation in cancer.", "link"=>"http://www.mendeley.com/research/cellextrinsic-effects-tumor-er-stress-imprint-myeloid-dendritic-cells-impair-cd8-t-cell-priming", "reader_count"=>39, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>1, "Researcher"=>12, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Student > Master"=>7, "Other"=>1, "Student > Bachelor"=>4, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>1, "Researcher"=>12, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Student > Master"=>7, "Other"=>1, "Student > Bachelor"=>4, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>6, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>14, "Medicine and Dentistry"=>6, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>2, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>14}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>6}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Chile"=>1}, "group_count"=>1}

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  • {"files"=>["https://ndownloader.figshare.com/files/522650"], "description"=>"<p>BMDC were cultured for 24 hrs in TERS<sup>cm</sup> or Veh<sup>cm</sup> from the tumor cell lines indicated, or media alone (Unstim). (<b>A</b>) RNA was isolated from BMDC and analyzed by RT-qPCR for UPR activation and proinflammatory cytokine gene transcription. Columns indicate fold increase in transcript level (RQ) of each treatment group. An Unstim control was set arbitrarily to 1. Error bars represent SEM of two biological replicates and are representative of six independent experiments. *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001, unpaired, two-tailed <i>t</i> test. BMDC cell lysates were analyzed for GRP78 expression by Western blot as indicated in Materials and Methods. Arginase activity was determined through the hydrolysis of L-arginine to L-ornithine. The amount of L-ornithine produced was determined using a colorimetric assay with ninhydrin, and was quantified using a ladder of known L-ornithine concentrations. The results are representative of two independent experiments. (<b>B</b>) Supernatants from BMDC in (A) were analyzed by cytometric bead array for presence of the indicated cytokines. *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001, unpaired, two-tailed <i>t</i> test. (<b>C</b>) RNA was isolated from BMDC and analyzed by RT-qPCR for <i>Il-10</i> transcription. Columns indicate fold increase in transcript level (RQ) of each treatment group. An Unstim control was set arbitrarily to 1. Error bars represent SEM of four biological replicates pooled from two independent experiments. BMDC supernatants were interrogated for IL-10; the dotted line indicates the threshold of detection.</p>", "links"=>[], "tags"=>["bmdc", "upregulate", "elements", "upr", "signaling", "pathways", "pro-inflammatory"], "article_id"=>193132, "categories"=>["Physiology", "Cancer", "Immunology"], "users"=>["Navin R. Mahadevan", "Veronika Anufreichik", "Jeffrey J. Rodvold", "Kevin T. Chiu", "Homero Sepulveda", "Maurizio Zanetti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0051845.g001", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TERS_imprinted_BMDC_upregulate_elements_of_the_UPR_signaling_pathways_and_produce_pro_inflammatory_cytokines_/193132", "title"=>"TERS-imprinted BMDC upregulate elements of the UPR signaling pathways and produce pro-inflammatory cytokines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-18 00:52:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/523465"], "description"=>"<p>(<b>A</b>) BMDC were cultured in TERS<sup>cm</sup> or Veh<sup>cm</sup> from B16.F10 tumor cells for 24 hrs and admixed with B16.F10 cells at a 1∶3 ratio (10<sup>4</sup> BMDC:3×10<sup>4</sup> B16.F10). Mixtures or B16.F10 cells alone (3×10<sup>4</sup>) were injected s.c. into the flanks of C57BL/6 mice and growth monitored by caliper measurement. Tumor size was expressed as volume (mm<sup>3</sup>). Error bars represent SEM of tumor size measurements pooled from all animals in the indicated experimental group. Statistical comparison was made between the following groups: [Tumor+TERS<sup>cm</sup> BMDC] and Tumor alone (top symbols) or [Tumor+Veh<sup>cm</sup> BMDC] (bottom symbols) on day 19. All other indicated comparisons were made between [Tumor+TERS<sup>cm</sup> BMDC] and [Tumor+Veh<sup>cm</sup> BMDC] groups. *<i>P</i><0.05, **<i>P</i><0.01, unpaired, two-tailed <i>t</i> test. (<b>B</b>) BMDC were cultured in TERS<sup>cm</sup> from TC1 tumor cells for 24 hrs and admixed with TC1.OVA cells at a 1∶3 ratio (10<sup>6</sup> BMDC:3×10<sup>6</sup> TC1.OVA). Mixtures or TC1.OVA cells alone (3×10<sup>6</sup>) were injected s.c. into the flanks of male C57BL/6 mice and tumor growth monitored by caliper measurement for 22 days. (<b>C</b>) B16.F10 tumor cells and TERS-imprinted BMDC were admixed as in (A) and injected s.c. into the medial thigh of C57BL/6 mice. Tumors were excised on day 14, measured by caliper (upper panel), and the percentage of tumor-infiltrating CD8<sup>+</sup> T lymphocytes (TIL) quantified by flow cytometry. The percentage of CD8<sup>+</sup> T lymphocytes was similarly determined in pooled draining inguinal lymph nodes (LN).</p>", "links"=>[], "tags"=>["bmdc"], "article_id"=>193961, "categories"=>["Physiology", "Cancer", "Immunology"], "users"=>["Navin R. Mahadevan", "Veronika Anufreichik", "Jeffrey J. Rodvold", "Kevin T. Chiu", "Homero Sepulveda", "Maurizio Zanetti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0051845.g007", "stats"=>{"downloads"=>3, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TERS_imprinted_BMDC_facilitate_tumor_growth_in_vivo_/193961", "title"=>"TERS-imprinted BMDC facilitate tumor growth <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-18 01:06:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/522745"], "description"=>"<p>BMDC were cultured for 24 h in TERS<sup>cm</sup> or Veh<sup>cm</sup> from the tumor cell lines indicated, or media alone (Unstim), and interrogated for the cell-surface expression of the indicated molecules by flow cytometry. Results are representative of at least three independent experiments.</p>", "links"=>[], "tags"=>["bmdc", "polarize", "mature"], "article_id"=>193237, "categories"=>["Physiology", "Cancer", "Immunology"], "users"=>["Navin R. Mahadevan", "Veronika Anufreichik", "Jeffrey J. Rodvold", "Kevin T. Chiu", "Homero Sepulveda", "Maurizio Zanetti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0051845.g002", "stats"=>{"downloads"=>2, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TERS_imprinted_BMDC_polarize_to_an_activated_mature_immunephenotype_/193237", "title"=>"TERS-imprinted BMDC polarize to an activated, mature immunephenotype.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-18 00:53:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/523012"], "description"=>"<p>Cross-presenting BMDC were prepared as in Fig. 3A. Unstimulated BMDC not fed OVA (Ag naïve) were used as a control. BMDC were then co-cultured with CFDA-SE-labeled CD8<sup>+</sup> OT-I transgenic T cells. After 96 hrs co-culture, CD8<sup>+</sup> T cells were interrogated for (<b>A</b>) expression of cell-surface activation markers, and (<b>B</b>) proliferation (CFDA-SE dilution) by flow cytometry. Results are representative of eight independent experiments. (<b>C</b>) CD8<sup>+</sup> T cells were cultured in TERS<sup>cm</sup> or Veh<sup>cm</sup> from B16.F10 tumor cells, or media alone (Unstim) for 24 hrs. The CD8<sup>+</sup> T cells were then labeled with CFDA-SE and incubated with OVA cross-presenting BMDC. After 96 hrs co-culture, CD8<sup>+</sup> T cells were interrogated for proliferation (CFDA-SE dilution) by flow cytometry.</p>", "links"=>[], "tags"=>["cells", "cross-primed", "ters-imprinted", "bmdc", "activated"], "article_id"=>193500, "categories"=>["Physiology", "Cancer", "Immunology"], "users"=>["Navin R. Mahadevan", "Veronika Anufreichik", "Jeffrey J. Rodvold", "Kevin T. Chiu", "Homero Sepulveda", "Maurizio Zanetti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0051845.g004", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CD8_T_cells_cross_primed_by_TERS_imprinted_BMDC_become_activated_but_do_not_proliferate_/193500", "title"=>"CD8<sup>+</sup> T cells cross-primed by TERS-imprinted BMDC become activated but do not proliferate.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-18 00:58:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/522877"], "description"=>"<p>(<b>A</b>) Schematic of the cross-presentation assay. BMDC were cultured in TERS<sup>cm</sup> or Veh<sup>cm</sup> from tumor cell lines, or media alone (Unstim), for 8 hrs after which OVA (1 mg/mL) was added directly to cultures for a further 16 hrs period. (<b>B</b>) Cross-presentation of the SIINFEKL/H2-K<sup>b</sup> complex was monitored using the 25.D1.16 antibody by flow cytometry. Results are representative of three independent experiments. (<b>C</b>) H2-K<sup>b</sup> expression was measured by flow cytometry. Results are representative of four independent experiments.</p>", "links"=>[], "tags"=>["cross-presentation", "ters-imprinted"], "article_id"=>193369, "categories"=>["Physiology", "Cancer", "Immunology"], "users"=>["Navin R. Mahadevan", "Veronika Anufreichik", "Jeffrey J. Rodvold", "Kevin T. Chiu", "Homero Sepulveda", "Maurizio Zanetti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0051845.g003", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Impaired_cross_presentation_by_TERS_imprinted_BMDC_/193369", "title"=>"Impaired cross-presentation by TERS-imprinted BMDC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-18 00:56:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/282505", "https://ndownloader.figshare.com/files/282575", "https://ndownloader.figshare.com/files/282611", "https://ndownloader.figshare.com/files/282645", "https://ndownloader.figshare.com/files/282683"], "description"=>"<div><p>Tumor-infiltrating myeloid cells, such as dendritic cells (BMDC), are key regulators of tumor growth. However, the tumor-derived signals polarizing BMDC to a phenotype that subverts cell-mediated anti-tumor immunity have yet to be fully elucidated. Addressing this unresolved problem we show that the tumor unfolded protein response (UPR) can function in a cell-extrinsic manner via the transmission of ER stress (TERS) to BMDC. TERS-imprinted BMDC upregulate the production of pro-inflammatory, tumorigenic cytokines but also the immunosuppressive enzyme arginase. Importantly, they downregulate cross-presentation of high-affinity antigen and fail to effectively cross-prime CD8<sup>+</sup> T cells, causing T cell activation without proliferation and similarly dominantly suppress cross-priming by bystander BMDC. Lastly, TERS-imprinted BMDC facilitate tumor growth <em>in vivo</em> with fewer tumor-infiltrating CD8<sup>+</sup> T cells. In sum, we demonstrate that tumor-borne ER stress imprints <em>ab initio</em> BMDC to a phenotype that recapitulates several of the inflammatory/suppressive characteristics ascribed to tumor-infiltrating myeloid cells, highlighting the tumor UPR as a critical controller of anti-tumor immunity and a new target for immune modulation in cancer.</p> </div>", "links"=>[], "tags"=>["cell-extrinsic", "effects", "er", "imprint", "myeloid", "dendritic", "cells", "impair", "priming"], "article_id"=>115703, "categories"=>["Physiology", "Cancer", "Immunology"], "users"=>["Navin R. Mahadevan", "Veronika Anufreichik", "Jeffrey J. Rodvold", "Kevin T. Chiu", "Homero Sepulveda", "Maurizio Zanetti"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0051845.s001", "https://dx.doi.org/10.1371/journal.pone.0051845.s002", "https://dx.doi.org/10.1371/journal.pone.0051845.s003", "https://dx.doi.org/10.1371/journal.pone.0051845.s004", "https://dx.doi.org/10.1371/journal.pone.0051845.s005"], "stats"=>{"downloads"=>12, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Cell_Extrinsic_Effects_of_Tumor_ER_Stress_Imprint_Myeloid_Dendritic_Cells_and_Impair_CD8_T_Cell_Priming__/115703", "title"=>"Cell-Extrinsic Effects of Tumor ER Stress Imprint Myeloid Dendritic Cells and Impair CD8<sup>+</sup> T Cell Priming", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-12-18 01:35:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/523361"], "description"=>"<p>(<b>A</b>) After 96-hr co-culture, CFDA-SE-labeled CD8<sup>+</sup> T cells were purified, the mRNA isolated and analyzed by RT-qPCR for transcription levels of the indicated genes. Columns indicate fold increase in transcript level (RQ) of each treatment group. An Unstim (+) control was set arbitrarily to 1. Error bars represent SEM of two biological replicates and are representative of four independent experiments. *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001, ns = not significant, unpaired, two-tailed <i>t</i> test. FOXP3 expression was interrogated by intracellular flow cytometry. (<b>B</b>) After 96 hr co-culture, CD8<sup>+</sup> T cells were interrogated for CD28 and LAG3 surface expression by flow cytometry. Results are representative of three independent experiments. (<b>C</b>) Supernatants from 96 hr co-cultures were interrogated for the presence of cytokines using the BD® Cytometric Bead Array assay. Results are pooled from two independent experiments.</p>", "links"=>[], "tags"=>["phenotypic", "cd8", "cells", "cross-primed", "ters-imprinted"], "article_id"=>193852, "categories"=>["Physiology", "Cancer", "Immunology"], "users"=>["Navin R. Mahadevan", "Veronika Anufreichik", "Jeffrey J. Rodvold", "Kevin T. Chiu", "Homero Sepulveda", "Maurizio Zanetti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0051845.g006", "stats"=>{"downloads"=>2, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcriptional_and_phenotypic_analysis_of_CD8_T_cells_cross_primed_by_TERS_imprinted_BMDC_/193852", "title"=>"Transcriptional and phenotypic analysis of CD8 T cells cross-primed by TERS-imprinted BMDC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-18 01:04:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/523216"], "description"=>"<p>BMDC were co-cultured with OT-I CD8<sup>+</sup> T cells as in Fig. 4. (<b>A</b>) CD8<sup>+</sup> OT-I T cells were co-cultured with SIINFEKL-pulsed TERS-imprinted BMDC and CD8<sup>+</sup> T cell proliferation was measured by CFDA-SE dilution. Results are representative of four independent experiments. (<b>B</b>) Recombinant mouse IL-2 was added at 30 or 100 U/mL to the co-cultures as indicated, and CD8<sup>+</sup> T cell proliferation was measured by CFDA-SE dilution. Results are representative of two independent experiments. (<b>C</b>) After 4-day co-culture, CFDA-SE-labeled CD8<sup>+</sup> T cells were recovered and rested for 2 days before restimulation with SIINFEKL-pulsed BMDC, with or without exogenous rmIL-2 (30 U/mL). CD8<sup>+</sup> T cell proliferation was measured by CFDA-SE dilution. Results are representative of two independent experiments. (<b>D</b>) L-arginine (L-arg, 2 mM) or L-norvaline (L-nor, 10 mM) was added to co-cultures and CD8<sup>+</sup> T cell proliferation was measured by CFDA-SE dilution. Results are representative of four independent experiments. (<b>E</b>) BMDC with (+) and without (−) OVA were co-cultured with CFDA-SE-labeled CD8<sup>+</sup> OT-I T cells at a 1∶1∶2.5 ratio as above and T cell proliferation was measured by CFDA-SE dilution. Results are representative of four independent experiments.</p>", "links"=>[], "tags"=>["proliferation-refractory", "phenotype", "cells", "cross-primed", "ters-imprinted", "bmdc", "rescued", "excess", "antigen"], "article_id"=>193697, "categories"=>["Physiology", "Cancer", "Immunology"], "users"=>["Navin R. Mahadevan", "Veronika Anufreichik", "Jeffrey J. Rodvold", "Kevin T. Chiu", "Homero Sepulveda", "Maurizio Zanetti"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0051845.g005", "stats"=>{"downloads"=>4, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_proliferation_refractory_phenotype_of_CD8_T_cells_cross_primed_TERS_imprinted_BMDC_can_be_rescued_by_excess_antigen_or_L_norvaline_but_not_by_addition_of_IL_2_/193697", "title"=>"The proliferation-refractory phenotype of CD8<sup>+</sup> T cells cross-primed TERS-imprinted BMDC can be rescued by excess antigen or L-norvaline, but not by addition of IL-2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-18 01:01:37"}

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Relative Metric

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