Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model
The axis of Programmed cell death-1 receptor (PD-1) with its ligand (PD-L1) plays a critical role in colorectal cancer (CRC) in escaping immune surveillance, and blocking this axis has been found to be effective in a subset of patients. Although blocking PD-L1 has been shown to be effective in 5–10%...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.706133/full |
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| author | Rinku Dutta Rinku Dutta Rinku Dutta Roukiah Khalil Roukiah Khalil Roukiah Khalil Karthick Mayilsamy Karthick Mayilsamy Karthick Mayilsamy Ryan Green Ryan Green Ryan Green Mark Howell Mark Howell Mark Howell Srinivas Bharadwaj Shyam S. Mohapatra Shyam S. Mohapatra Shyam S. Mohapatra Subhra Mohapatra Subhra Mohapatra Subhra Mohapatra |
| author_facet | Rinku Dutta Rinku Dutta Rinku Dutta Roukiah Khalil Roukiah Khalil Roukiah Khalil Karthick Mayilsamy Karthick Mayilsamy Karthick Mayilsamy Ryan Green Ryan Green Ryan Green Mark Howell Mark Howell Mark Howell Srinivas Bharadwaj Shyam S. Mohapatra Shyam S. Mohapatra Shyam S. Mohapatra Subhra Mohapatra Subhra Mohapatra Subhra Mohapatra |
| author_sort | Rinku Dutta |
| collection | DOAJ |
| description | The axis of Programmed cell death-1 receptor (PD-1) with its ligand (PD-L1) plays a critical role in colorectal cancer (CRC) in escaping immune surveillance, and blocking this axis has been found to be effective in a subset of patients. Although blocking PD-L1 has been shown to be effective in 5–10% of patients, the majority of the cohorts show resistance to this checkpoint blockade (CB) therapy. Multiple factors assist in the growth of resistance to CB, among which T cell exhaustion and immunosuppressive effects of immune cells in the tumor microenvironment (TME) play a critical role along with other tumor intrinsic factors. We have previously shown the polyketide antibiotic, Mithramycin-A (Mit-A), an effective agent in killing cancer stem cells (CSCs) in vitro and in vivo in a subcutaneous murine model. Since TME plays a pivotal role in CB therapy, we tested the immunomodulatory efficacy of Mit-A with anti-PD-L1 mAb (αPD-L1) combination therapy in an immunocompetent MC38 syngeneic orthotopic CRC mouse model. Tumors and spleens were analyzed by flow cytometry for the distinct immune cell populations affected by the treatment, in addition to RT-PCR for tumor samples. We demonstrated the combination treatment decreases tumor growth, thus increasing the effectiveness of the CB. Mit-A in the presence of αPD-L1 significantly increased CD8+ T cell infiltration and decreased immunosuppressive granulocytic myeloid-derived suppressor cells and anti-inflammatory macrophages in the TME. Our results revealed Mit-A in combination with αPD-L1 has the potential for augmented CB therapy by turning an immunologically “cold” into “hot” TME in CRC. |
| first_indexed | 2024-12-14T22:23:03Z |
| format | Article |
| id | doaj.art-3a5f47449b2a4cc4b4b873fd52643ecc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T22:23:03Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-3a5f47449b2a4cc4b4b873fd52643ecc2022-12-21T22:45:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-07-011210.3389/fimmu.2021.706133706133Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine ModelRinku Dutta0Rinku Dutta1Rinku Dutta2Roukiah Khalil3Roukiah Khalil4Roukiah Khalil5Karthick Mayilsamy6Karthick Mayilsamy7Karthick Mayilsamy8Ryan Green9Ryan Green10Ryan Green11Mark Howell12Mark Howell13Mark Howell14Srinivas Bharadwaj15Shyam S. Mohapatra16Shyam S. Mohapatra17Shyam S. Mohapatra18Subhra Mohapatra19Subhra Mohapatra20Subhra Mohapatra21James A. Haley Veterans’ Hospital, Tampa, FL, United StatesDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesCenter for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesJames A. Haley Veterans’ Hospital, Tampa, FL, United StatesDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesCenter for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesJames A. Haley Veterans’ Hospital, Tampa, FL, United StatesDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesCenter for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesJames A. Haley Veterans’ Hospital, Tampa, FL, United StatesCenter for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesDepartment of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesJames A. Haley Veterans’ Hospital, Tampa, FL, United StatesCenter for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesDepartment of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesDepartment of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesJames A. Haley Veterans’ Hospital, Tampa, FL, United StatesCenter for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesDepartment of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesJames A. Haley Veterans’ Hospital, Tampa, FL, United StatesDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesCenter for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesThe axis of Programmed cell death-1 receptor (PD-1) with its ligand (PD-L1) plays a critical role in colorectal cancer (CRC) in escaping immune surveillance, and blocking this axis has been found to be effective in a subset of patients. Although blocking PD-L1 has been shown to be effective in 5–10% of patients, the majority of the cohorts show resistance to this checkpoint blockade (CB) therapy. Multiple factors assist in the growth of resistance to CB, among which T cell exhaustion and immunosuppressive effects of immune cells in the tumor microenvironment (TME) play a critical role along with other tumor intrinsic factors. We have previously shown the polyketide antibiotic, Mithramycin-A (Mit-A), an effective agent in killing cancer stem cells (CSCs) in vitro and in vivo in a subcutaneous murine model. Since TME plays a pivotal role in CB therapy, we tested the immunomodulatory efficacy of Mit-A with anti-PD-L1 mAb (αPD-L1) combination therapy in an immunocompetent MC38 syngeneic orthotopic CRC mouse model. Tumors and spleens were analyzed by flow cytometry for the distinct immune cell populations affected by the treatment, in addition to RT-PCR for tumor samples. We demonstrated the combination treatment decreases tumor growth, thus increasing the effectiveness of the CB. Mit-A in the presence of αPD-L1 significantly increased CD8+ T cell infiltration and decreased immunosuppressive granulocytic myeloid-derived suppressor cells and anti-inflammatory macrophages in the TME. Our results revealed Mit-A in combination with αPD-L1 has the potential for augmented CB therapy by turning an immunologically “cold” into “hot” TME in CRC.https://www.frontiersin.org/articles/10.3389/fimmu.2021.706133/fullPD-L1orthotopic tumorcolorectal cancerMithramycin-Acombination therapy |
| spellingShingle | Rinku Dutta Rinku Dutta Rinku Dutta Roukiah Khalil Roukiah Khalil Roukiah Khalil Karthick Mayilsamy Karthick Mayilsamy Karthick Mayilsamy Ryan Green Ryan Green Ryan Green Mark Howell Mark Howell Mark Howell Srinivas Bharadwaj Shyam S. Mohapatra Shyam S. Mohapatra Shyam S. Mohapatra Subhra Mohapatra Subhra Mohapatra Subhra Mohapatra Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model Frontiers in Immunology PD-L1 orthotopic tumor colorectal cancer Mithramycin-A combination therapy |
| title | Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model |
| title_full | Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model |
| title_fullStr | Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model |
| title_full_unstemmed | Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model |
| title_short | Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model |
| title_sort | combination therapy of mithramycin a and immune checkpoint inhibitor for the treatment of colorectal cancer in an orthotopic murine model |
| topic | PD-L1 orthotopic tumor colorectal cancer Mithramycin-A combination therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.706133/full |
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