Immune modulation by combination type I interferon and checkpoint blockade therapy in murine urothelial carcinoma

Abstract

Abstract 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 recruitment and activation of immune cells in murine bladder cancer tumors, and makes them more responsive to anti-PD-1 mAb therapy. To incite an IFN-driven inflammatory response, poly(I:C) was given to murine MB49 bladder cancer tumors peritumorally alone and in combination with anti-PD-1 mAb to determine effects on tumor growth and animal survival. IFN induction in MB49 tumors significantly inhibited tumor growth. This response was reliant on both innate and adaptive immune subsets, shown in the increased influx of intratumoral Ly6G+ neutrophils and the increase in IFNy+CD8 T cells. In addition, depleting specific immune cell subsets indicated that no one type of immune cell was critical for the IFN-mediated anti-tumor response. When used in combination with anti-PD-1 mAb, poly(I:C) prolonged mouse survival and enriched gene pathways involved in metabolism, extracellular matrix formation and organization, and PI3K and AKT signaling. To examine effects of IFN-I in BCG-unresponsive patients, tumor samples were analyzed for RNA expression and immunohistochemical (IHC) staining both before and after treatment with adenoviral interferon-α. Among these samples, 25% showed increased expression of T cell and checkpoint markers, similarly reflected in IHC analysis. Our findings suggest type I IFN grooms the tumor-immune landscape in bladder cancer by activating both innate and adaptive immune cells.