Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism
Abstract Background TNF receptor family agonists and checkpoint blockade combination therapies lead to minimal tumor clearance of poorly immunogenic tumors. Therefore, a need to enhance the efficacy of this combination therapy arises. Antigen-presenting cells (APCs) present antigen to T cells and st...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2019-11-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0786-7 |
| _version_ | 1819203885755006976 |
|---|---|
| author | Jaina M. Patel Zhihua Cui Zhi-Fa Wen Catherine T. Dinh Hong-Ming Hu |
| author_facet | Jaina M. Patel Zhihua Cui Zhi-Fa Wen Catherine T. Dinh Hong-Ming Hu |
| author_sort | Jaina M. Patel |
| collection | DOAJ |
| description | Abstract Background TNF receptor family agonists and checkpoint blockade combination therapies lead to minimal tumor clearance of poorly immunogenic tumors. Therefore, a need to enhance the efficacy of this combination therapy arises. Antigen-presenting cells (APCs) present antigen to T cells and steer the immune response through chemokine and cytokine secretion. DRibbles (DR) are tumor-derived autophagosomes containing tumor antigens and innate inflammatory adjuvants. Methods Using preclinical murine lung and pancreatic cancer models, we assessed the triple combination therapy of GITR agonist and PD-1 blocking antibodies with peritumoral injections of DRibbles-pulsed-bone marrow cells (BMCs), which consisted mainly of APCs, or CD103+ cross-presenting dendritic cells (DCs). Immune responses were assessed by flow cytometry. FTY720 was used to prevent T-cell egress from lymph nodes to assess lymph node involvement, and MHC-mismatched-BMCs were used to assess the necessity of antigen presentation by the peritumorally-injected DR-APCs. Results Tritherapy increased survival and cures in tumor-bearing mice compared to combined antibody therapy or peritumoral DR-BMCs alone. Peritumorally-injected BMCs remained within the tumor for at least 14 days and tritherapy efficacy was dependent on both CD4+ and CD8+ T cells. Although the overall percent of tumor-infiltrating T cells remained similar, tritherapy increased the ratio of effector CD4+ T cells-to-regulatory T cells, CD4+ T-cell cytokine production and proliferation, and CD8+ T-cell cytolytic activity in the tumor. Despite tritherapy-induced T-cell activation and cytolytic activity in lymph nodes, this T-cell activation was not required for tumor regression and enhanced survival. Replacement of DR-BMCs with DR-pulsed-DCs in the tritherapy led to similar antitumor effects, whereas replacement with DRibbles was less effective but delayed tumor growth. Interestingly, peritumoral administration of DR-pulsed MHC-mismatched-APCs in the tritherapy led to similar antitumor effects as MHC-matched-APCs, indicating that the observed enhanced antitumor effect was mediated independently of antigen presentation by the administered APCs. Conclusions Overall, these results demonstrate that peritumoral DR-pulsed-BMC/DC administration synergizes with GITR agonist and PD-1 blockade to locally modulate and sustain tumor effector T-cell responses independently of T cell priming and perhaps through innate inflammatory modulations mediated by the DRibbles adjuvant. We offer a unique approach to modify the tumor microenvironment to benefit T-cell-targeted immunotherapies. |
| first_indexed | 2024-12-23T04:27:02Z |
| format | Article |
| id | doaj.art-fa030b43b66f40f1b32cf6d32683938d |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-23T04:27:02Z |
| publishDate | 2019-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-fa030b43b66f40f1b32cf6d32683938d2022-12-21T18:00:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-11-017111810.1186/s40425-019-0786-7Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanismJaina M. Patel0Zhihua Cui1Zhi-Fa Wen2Catherine T. Dinh3Hong-Ming Hu4Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer CenterLaboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer CenterLaboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer CenterLaboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer CenterLaboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer CenterAbstract Background TNF receptor family agonists and checkpoint blockade combination therapies lead to minimal tumor clearance of poorly immunogenic tumors. Therefore, a need to enhance the efficacy of this combination therapy arises. Antigen-presenting cells (APCs) present antigen to T cells and steer the immune response through chemokine and cytokine secretion. DRibbles (DR) are tumor-derived autophagosomes containing tumor antigens and innate inflammatory adjuvants. Methods Using preclinical murine lung and pancreatic cancer models, we assessed the triple combination therapy of GITR agonist and PD-1 blocking antibodies with peritumoral injections of DRibbles-pulsed-bone marrow cells (BMCs), which consisted mainly of APCs, or CD103+ cross-presenting dendritic cells (DCs). Immune responses were assessed by flow cytometry. FTY720 was used to prevent T-cell egress from lymph nodes to assess lymph node involvement, and MHC-mismatched-BMCs were used to assess the necessity of antigen presentation by the peritumorally-injected DR-APCs. Results Tritherapy increased survival and cures in tumor-bearing mice compared to combined antibody therapy or peritumoral DR-BMCs alone. Peritumorally-injected BMCs remained within the tumor for at least 14 days and tritherapy efficacy was dependent on both CD4+ and CD8+ T cells. Although the overall percent of tumor-infiltrating T cells remained similar, tritherapy increased the ratio of effector CD4+ T cells-to-regulatory T cells, CD4+ T-cell cytokine production and proliferation, and CD8+ T-cell cytolytic activity in the tumor. Despite tritherapy-induced T-cell activation and cytolytic activity in lymph nodes, this T-cell activation was not required for tumor regression and enhanced survival. Replacement of DR-BMCs with DR-pulsed-DCs in the tritherapy led to similar antitumor effects, whereas replacement with DRibbles was less effective but delayed tumor growth. Interestingly, peritumoral administration of DR-pulsed MHC-mismatched-APCs in the tritherapy led to similar antitumor effects as MHC-matched-APCs, indicating that the observed enhanced antitumor effect was mediated independently of antigen presentation by the administered APCs. Conclusions Overall, these results demonstrate that peritumoral DR-pulsed-BMC/DC administration synergizes with GITR agonist and PD-1 blockade to locally modulate and sustain tumor effector T-cell responses independently of T cell priming and perhaps through innate inflammatory modulations mediated by the DRibbles adjuvant. We offer a unique approach to modify the tumor microenvironment to benefit T-cell-targeted immunotherapies.http://link.springer.com/article/10.1186/s40425-019-0786-7GITRPD-1Antigen presenting cellsDendritic cellsPeritumoral injectionTumor microenvironment |
| spellingShingle | Jaina M. Patel Zhihua Cui Zhi-Fa Wen Catherine T. Dinh Hong-Ming Hu Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism Journal for ImmunoTherapy of Cancer GITR PD-1 Antigen presenting cells Dendritic cells Peritumoral injection Tumor microenvironment |
| title | Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism |
| title_full | Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism |
| title_fullStr | Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism |
| title_full_unstemmed | Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism |
| title_short | Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism |
| title_sort | peritumoral administration of dribbles pulsed antigen presenting cells enhances the antitumor efficacy of anti gitr and anti pd 1 antibodies via an antigen presenting independent mechanism |
| topic | GITR PD-1 Antigen presenting cells Dendritic cells Peritumoral injection Tumor microenvironment |
| url | http://link.springer.com/article/10.1186/s40425-019-0786-7 |
| work_keys_str_mv | AT jainampatel peritumoraladministrationofdribblespulsedantigenpresentingcellsenhancestheantitumorefficacyofantigitrandantipd1antibodiesviaanantigenpresentingindependentmechanism AT zhihuacui peritumoraladministrationofdribblespulsedantigenpresentingcellsenhancestheantitumorefficacyofantigitrandantipd1antibodiesviaanantigenpresentingindependentmechanism AT zhifawen peritumoraladministrationofdribblespulsedantigenpresentingcellsenhancestheantitumorefficacyofantigitrandantipd1antibodiesviaanantigenpresentingindependentmechanism AT catherinetdinh peritumoraladministrationofdribblespulsedantigenpresentingcellsenhancestheantitumorefficacyofantigitrandantipd1antibodiesviaanantigenpresentingindependentmechanism AT hongminghu peritumoraladministrationofdribblespulsedantigenpresentingcellsenhancestheantitumorefficacyofantigitrandantipd1antibodiesviaanantigenpresentingindependentmechanism |