TY - JOUR
T1 - Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation
AU - Plote, Devin
AU - Choi, Woonyoung
AU - Mokkapati, Sharada
AU - Sundi, Debasish
AU - Ferguson, James E.
AU - Duplisea, Jon
AU - Parker, Nigel R.
AU - Yla-Herttuala, Seppo
AU - Committee, SUO CTC Bladder
AU - McConkey, David
AU - Schluns, Kimberly S.
AU - Dinney, Colin P.
N1 - Funding Information:
This research was supported in part by FKD Therapies Oy (Kuopio, Finland), A.I. Virtanen Institute for Molecular Sciences (Kuopio, Finland), and grants from National Institutes of Health/National Cancer Institute (P50 CA091846), MD Anderson CCSG program (P30 016672), and the Cancer Prevention Research Institute of Texas (RP160188 to K.S.S) We are grateful to Dr. Xiaoping Su and MD Anderson SMF Core Laboratory for their work in sequencing, aligning, and normalizing the RNA data; Dr. William Kim and his lab at University of North Carolina Chappell Hill for their donation of BBN and UPPL-mouse-derived murine bladder cancer cell lines and discussion for experimental aid; Shelley Herbrich for help with GSEA and statistical analysis; Rosa Santana, Sarai Rivas, Shweta Hedge for invaluable discussions and experimental aid; and MD Anderson Department of Scientific Publications, specifically Erica Goodoff for preliminary editing of this manuscript. Special thanks to the Clinical Investigators associated with the Society of Urologic Oncology Clinical Trials Consortium and who participated in the Phase 2 study, including: Dr. Trinity Bivalacqua of Johns Hopkins Medical Center, Dr. Stephen Boorjian of the Mayo Clinic, Dr. Daniel Canter of the Oschner Clinic, Dr. Tracey Downs of the University of Wisconsin Medical Center, Dr. Leonard Gomella of Thomas Jefferson University, Dr. Robert Grubb III of the Medical University of South Carolina, Dr. Brant Inman of Duke University Medical Center, Dr. Ashish Kamat of MD Anderson Cancer Center, Dr. Larry Karsh of the Urology Center of Colorado, Dr. Tracey Krupski of the University of Virginia, Dr. Seth Lerner of Baylor College of Medicine, Dr. Yair Lotan of the University of Texas Southwestern Medical Center, Dr. Matthew Milowsky of the Univeristy of North Carolina Medical Center, Dr. Kenneth Ogan of Emory Clinic, Dr. Neal Shore of the Carolina Urologic Research Center, Dr. Robert Svatek of the University of Texas Health Science Center San Antonio, and Dr. Michael Woods of Loyola University Medical Center.
Funding Information:
This research was supported in part by FKD Therapies Oy (Kuopio, Finland), A.I. Virtanen Institute for Molecular Sciences (Kuopio, Finland), and grants from National Institutes of Health/National Cancer Institute (P50 CA091846), MD Anderson CCSG program (P30 016672), and the Cancer Prevention Research Institute of Texas (RP160188 to K.S.S)
Publisher Copyright:
© 2019, © 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.
PY - 2019/5/4
Y1 - 2019/5/4
N2 - 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.
AB - 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.
KW - PD-1
KW - bladder cancer
KW - immune microenvironment
KW - interferon
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U2 - 10.1080/2162402X.2019.1577125
DO - 10.1080/2162402X.2019.1577125
M3 - Article
C2 - 31069136
AN - SCOPUS:85063890992
SN - 2162-4011
VL - 8
JO - OncoImmunology
JF - OncoImmunology
IS - 5
M1 - e1577125
ER -