Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation
Type I interferon (IFN-I) has potent anti-tumor effects against urothelial carcinoma (UC) and may be an alternative treatment option for patients who do not respond to Bacillus Calmette-Guerin. However, the mechanisms that mediate the IFN-I-stimulated immune responses against UC have yet to be eluci...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-05-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2019.1577125 |
| _version_ | 1828262713450561536 |
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| author | Devin Plote Woonyoung Choi Sharada Mokkapati Debasish Sundi James E Ferguson Jon Duplisea Nigel R. Parker Seppo Yla-Herttuala SUO CTC Bladder Committee David McConkey Kimberly S. Schluns Colin P. Dinney |
| author_facet | Devin Plote Woonyoung Choi Sharada Mokkapati Debasish Sundi James E Ferguson Jon Duplisea Nigel R. Parker Seppo Yla-Herttuala SUO CTC Bladder Committee David McConkey Kimberly S. Schluns Colin P. Dinney |
| author_sort | Devin Plote |
| collection | DOAJ |
| description | Type I interferon (IFN-I) has potent anti-tumor effects against urothelial carcinoma (UC) and may be an alternative treatment option for patients who do not respond to Bacillus Calmette-Guerin. However, the mechanisms that mediate the IFN-I-stimulated immune responses against UC have yet to be elucidated. Herein, we evaluated the anti-tumor mechanisms of IFN-I in UC in human patients and in mice. Patient tumors from a Phase I clinical trial with adenoviral interferon-α (Ad-IFNα/Syn3) showed increased expression of T cell and checkpoint markers following treatment with Ad-IFNα/Syn3 by RNAseq and immunohistochemistry analysis in 25% of patients. In mice, peritumoral injections of poly(I:C) into MB49 UC tumors was used to incite an IFN-driven inflammatory response that significantly inhibited tumor growth. IFN-I engaged both innate and adaptive cells, seen in increased intratumoral CD8 T cells, NK cells, and CD11b+Ly6G+ cells, but tumor inhibition was not reliant on any one immune cell type. Nonetheless, poly(I:C)-mediated tumor regression and change in the myeloid cell landscape was dependent on IL-6. Mice were also treated with poly(I:C) in combination with anti-PD-1 monoclonal antibody (mAb) to assess for additional benefit to tumor growth and animal survival. When used in combination with anti-PD-1 mAb, IFN-I stimulation prolonged survival, coinciding with inhibition of angiogenesis and enriched gene signatures of metabolism, extracellular matrix organization, and MAPK/AKT signaling. Altogether, these findings suggest IFN-I’s immune-driven antitumor response in UC is mediated by IL-6 and a collaboration of immune cells, and its use in combination with checkpoint blockade therapy can increase clinical benefit. |
| first_indexed | 2024-04-13T04:00:10Z |
| format | Article |
| id | doaj.art-8f2fc5baf21f453bade61adaf369e1f7 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-04-13T04:00:10Z |
| publishDate | 2019-05-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-8f2fc5baf21f453bade61adaf369e1f72022-12-22T03:03:30ZengTaylor & Francis GroupOncoImmunology2162-402X2019-05-018510.1080/2162402X.2019.15771251577125Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activationDevin Plote0Woonyoung Choi1Sharada Mokkapati2Debasish Sundi3James E Ferguson4Jon Duplisea5Nigel R. Parker6Seppo Yla-Herttuala7SUO CTC Bladder Committee8David McConkey9Kimberly S. Schluns10Colin P. Dinney11The University of Texas MD Anderson Cancer Center; University of Texas Health Graduate School of Biomedical Sciences at HoustonJohns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, School of MedicineThe University of Texas MD Anderson Cancer CenterThe Ohio State University Comprehensive Cancer CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterHamesman, Ltd., EdgwareUniversity of Eastern FinlandSociety of Urologic Oncology Clinical Trials ConsortiumJohns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, School of MedicineThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterType I interferon (IFN-I) has potent anti-tumor effects against urothelial carcinoma (UC) and may be an alternative treatment option for patients who do not respond to Bacillus Calmette-Guerin. However, the mechanisms that mediate the IFN-I-stimulated immune responses against UC have yet to be elucidated. Herein, we evaluated the anti-tumor mechanisms of IFN-I in UC in human patients and in mice. Patient tumors from a Phase I clinical trial with adenoviral interferon-α (Ad-IFNα/Syn3) showed increased expression of T cell and checkpoint markers following treatment with Ad-IFNα/Syn3 by RNAseq and immunohistochemistry analysis in 25% of patients. In mice, peritumoral injections of poly(I:C) into MB49 UC tumors was used to incite an IFN-driven inflammatory response that significantly inhibited tumor growth. IFN-I engaged both innate and adaptive cells, seen in increased intratumoral CD8 T cells, NK cells, and CD11b+Ly6G+ cells, but tumor inhibition was not reliant on any one immune cell type. Nonetheless, poly(I:C)-mediated tumor regression and change in the myeloid cell landscape was dependent on IL-6. Mice were also treated with poly(I:C) in combination with anti-PD-1 monoclonal antibody (mAb) to assess for additional benefit to tumor growth and animal survival. When used in combination with anti-PD-1 mAb, IFN-I stimulation prolonged survival, coinciding with inhibition of angiogenesis and enriched gene signatures of metabolism, extracellular matrix organization, and MAPK/AKT signaling. Altogether, these findings suggest IFN-I’s immune-driven antitumor response in UC is mediated by IL-6 and a collaboration of immune cells, and its use in combination with checkpoint blockade therapy can increase clinical benefit.http://dx.doi.org/10.1080/2162402X.2019.1577125pd-1interferonbladder cancerimmune microenvironment |
| spellingShingle | Devin Plote Woonyoung Choi Sharada Mokkapati Debasish Sundi James E Ferguson Jon Duplisea Nigel R. Parker Seppo Yla-Herttuala SUO CTC Bladder Committee David McConkey Kimberly S. Schluns Colin P. Dinney Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation OncoImmunology pd-1 interferon bladder cancer immune microenvironment |
| title | Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation |
| title_full | Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation |
| title_fullStr | Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation |
| title_full_unstemmed | Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation |
| title_short | Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation |
| title_sort | inhibition of urothelial carcinoma through targeted type i interferon mediated immune activation |
| topic | pd-1 interferon bladder cancer immune microenvironment |
| url | http://dx.doi.org/10.1080/2162402X.2019.1577125 |
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