Blocking indolamine-2,3-dioxygenase rebound immune suppression boosts antitumor effects of radio-immunotherapy in murine models and spontaneous canine malignancies

Arta M Monjazeb, Michael S Kent, Steven K. Grossenbacher, Christine Mall, Anthony E. Zamora, Annie Mirsoian, Mingyi Chen, Amir Kol, Stephen L. Shiao, Abhinav Reddy, Julian R Perks, William T Culp, Ellen E. Sparger, Robert J Canter, Gail D. Sckisel, William J Murphy

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Purpose: Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. Experimental Design: We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial. Results: In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8+ T-cell-dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. Conclusions: These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation.

Original languageEnglish (US)
Pages (from-to)4328-4340
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number17
DOIs
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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