Immune Modulation by Combination Type I Interferon and Checkpoint Blockade Therapy in Murine Urothelial Carcinoma

Identification: Plote, Devin


Description

 

Immune Modulation by Combination Type I Interferon and Checkpoint Blockade Therapy in Murine Urothelial Carcinoma
 
Devin Plote1, David McConkey3, Kimberly S. Schluns4, Colin P. Dinney2
1Cancer Biology Graduate Program, University of Texas MD Anderson Cancer Center, Houston, TX; 2 Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX; 3James Buchanan Brady Urological Institute, Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD; 4Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX
 
Type I interferon (IFN) has potent antitumor effects in bladder cancer and provides an essential alternative treatment option for patients who do not respond to Bacillus Calmette-Guerin (BCG). However, the mechanism of the IFN-stimulated immune response in bladder cancer is not well understood.  We hypothesized that type I IFN enhances immune cell recruitment and cytolytic activity in murine bladder cancer tumors, and making them more responsive to therapy with anti-PD-1 checkpoint inhibition. To test this hypothesis, murine MB49 bladder cancer tumors were treated with peritumoral injections of poly(I:C) to incite an IFN-driven inflammatory response. Mice were also treated with poly(I:C) in combination with anti-PD-1 monoclonal antibody to determine synergistic effects on tumor growth and animal survival. IFN induction in MB49 tumors initiated a cytotoxic immune response in the tumor microenvironment and significantly inhibited tumor growth. This response was reliant on both innate and adaptive immune subsets, which was reflected in the increased influx of intratumoral Ly6G+ neutrophils, increase in CD8 T cell cytolytic function, and decreased poly(I:C) efficacy when Thy1.2+ cells were depleted. When used in combination with anti-PD-1 monoclonal antibody, IFN stimulation prolonged mouse survival. To examine effects of IFN-I in BCG-unresponsive patients, tumor samples were analyzed for RNA expression and immunohistochemical staining both before and after treatment with adenoviral interferon-α. Among these samples, 25% showed increased expression of T cells and checkpoint markers, which was also reflected in immunohistochemistry analysis. Our findings suggest type I IFN grooms the tumor-immune landscape in bladder cancer by recruiting activated immune cells, priming tumors for efficacious treatment by checkpoint blockade therapy.

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