Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy
Abstract Background We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4+ and myeloid-derived suppressor cells (MDSCs) in the tumor microenviron...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2017-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-017-0266-x |
| _version_ | 1819168169550413824 |
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| author | Rajeev Shrimali Shamim Ahmad Zuzana Berrong Grigori Okoev Adelaida Matevosyan Ghazaleh Shoja E. Razavi Robert Petit Seema Gupta Mikayel Mkrtichyan Samir N. Khleif |
| author_facet | Rajeev Shrimali Shamim Ahmad Zuzana Berrong Grigori Okoev Adelaida Matevosyan Ghazaleh Shoja E. Razavi Robert Petit Seema Gupta Mikayel Mkrtichyan Samir N. Khleif |
| author_sort | Rajeev Shrimali |
| collection | DOAJ |
| description | Abstract Background We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4+ and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment. Methods Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations. Results We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4+ and CD8+ T cells along with a decrease of inhibitory cells. Conclusion To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall efficacy of cancer immunotherapy. |
| first_indexed | 2024-12-22T18:59:20Z |
| format | Article |
| id | doaj.art-61811cabb1744d598da3309ba03659cc |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-22T18:59:20Z |
| publishDate | 2017-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-61811cabb1744d598da3309ba03659cc2022-12-21T18:15:59ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262017-08-01511910.1186/s40425-017-0266-xAgonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapyRajeev Shrimali0Shamim Ahmad1Zuzana Berrong2Grigori Okoev3Adelaida Matevosyan4Ghazaleh Shoja E. Razavi5Robert Petit6Seema Gupta7Mikayel Mkrtichyan8Samir N. Khleif9Augusta University, Georgia Cancer CenterAugusta University, Georgia Cancer CenterAugusta University, Georgia Cancer CenterAugusta University, Georgia Cancer CenterAugusta University, Georgia Cancer CenterAugusta University, Georgia Cancer CenterAdvaxis ImmunotherapiesAugusta University, Georgia Cancer CenterAugusta University, Georgia Cancer CenterAugusta University, Georgia Cancer CenterAbstract Background We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4+ and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment. Methods Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations. Results We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4+ and CD8+ T cells along with a decrease of inhibitory cells. Conclusion To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall efficacy of cancer immunotherapy.http://link.springer.com/article/10.1186/s40425-017-0266-xListeria vaccineLm-LLO-E7Anti-GITR antibodyCo-stimulationImmune toleranceImmunotherapy |
| spellingShingle | Rajeev Shrimali Shamim Ahmad Zuzana Berrong Grigori Okoev Adelaida Matevosyan Ghazaleh Shoja E. Razavi Robert Petit Seema Gupta Mikayel Mkrtichyan Samir N. Khleif Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy Journal for ImmunoTherapy of Cancer Listeria vaccine Lm-LLO-E7 Anti-GITR antibody Co-stimulation Immune tolerance Immunotherapy |
| title | Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy |
| title_full | Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy |
| title_fullStr | Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy |
| title_full_unstemmed | Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy |
| title_short | Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy |
| title_sort | agonist anti gitr antibody significantly enhances the therapeutic efficacy of listeria monocytogenes based immunotherapy |
| topic | Listeria vaccine Lm-LLO-E7 Anti-GITR antibody Co-stimulation Immune tolerance Immunotherapy |
| url | http://link.springer.com/article/10.1186/s40425-017-0266-x |
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