Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation

Abstract

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.

Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy

“…The same report was noted for polyinosinic:polycytidylic acid (poly(I:C)), a TLR3 agonist, also in combination with BCG in models of BCa [192,193]. Moreover, poly(I:C) treatment was efficient to enhance the anti-PD-1 response in a NMIBC model [193]. These results indicate that TLR agonists could be further investigated for the treatment of BCa to complement or replace BCG in NMIBC, or to improve ICIs in advanced BCa.…”

“…A clinical study on NMIBC patients indicated that a TLR7 agonist, in combination with BCG, induced a significant increase of cytokines in the urine of patients and increased clinical responses [191]. The same report was noted for polyinosinic:polycytidylic acid (poly(I:C)), a TLR3 agonist, also in combination with BCG in models of BCa [192,193]. Moreover, poly(I:C) treatment was efficient to enhance the anti-PD-1 response in a NMIBC model [193].…”

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

“…A primary goal of this study was to determine whether the antitumor efficacy of BCG in urothelial cancer models could be enhanced by engineering excess production of the STING agonist, c-di-AMP. In light of studies showing elevated Type I IFN and NF-κB-mediated antitumor host immune responses in NMIBC patients who respond to BCG [55][56][57] , we reasoned that adding STING agonist overexpression to traditional BCG might further increase these favorable immune parameters. c-di-AMP is a STING agonist produced naturally in low levels by BCG (where it serves as a second messenger signaling molecule in microbial physiology), that is closely related to the natural human STING ligand, cGAMP 58,59 .…”

Unraveling the Mechanism of the Antitumor Activity of Bacillus Calmette-Guérin

“…A recently completed phase 3 clinical trial demonstrated that rAd-IFNα/Syn3 monotherapy had a complete response rate of 53.4% at 3 mo and 24.3% at 12 mo among 103 patients with carinoma in situ containing BCG-unresponsive disease [8] . In preclinical and clinical correlative studies, tumor-infiltrating lymphocytes, particularly CD8 + lymphocytes, increased after treatment [9] . Oncolytic adenovirus CG0070 also had antitumor activity in a cohort of bladder cancer patients unsuccessfully treated with BCG [10] .…”

“…To truly achieve synergy with CPI, combination agents capable of recruiting [8]. In preclinical and clinical correlative studies, tumor-infiltrating lymphocytes, particularly CD8 + lymphocytes, increased after treatment [9]. Oncolytic adenovirus CG0070 also had antitumor activity in a cohort of bladder cancer patients unsuccessfully treated with BCG [10].…”