Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies

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 þ 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 CD8þ 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. Clin Cancer Res; 22(17); 4328-40. Ó2016 AACR.

Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols

“…After a large inflammatory insult, MDSC proliferation and M2 polarization are enhanced, and such changes can be harmful to the antitumor immune response, an effect termed rebound immune suppression (31). M2 macrophages are reported to limit the response to radiation (28); a large increase in macrophages and MDSCs and a trend toward the M2 phenotype were observed following ablation concurrent with immunotherapy.…”

Stimulating Innate Immunity to Enhance Radiation Therapy–Induced Tumor Control

“…In the clinical studies of radiotherapy combined with CpG described above, patients whose tumors induced immunosuppressive regulatory Tregs responded poorly to therapy and had a poor prognosis 107 . Radiotherapy combined with CpG was found to upregulate indolamine 2,3-dioxygenase (IDO) expression, which was termed “rebound immune suppression” 105 . This upregulation of IDO occured in response to the inflammation induced by radiotherapy and TLR activation, generating an immune suppression that included Tregs.…”

Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’

“…IDO1 blockade can deepen responses to ‘immunogenic’ chemotherapy and radiotherapy [30, 143], although such combinations have yet to be pursued as energetically as immune checkpoint therapy so far. Here benefits of the combination may relate to mutagenesis and cell death produced by chemo/radiotherapy, thereby yielding higher antigenicity to which the adaptive immune system can react.…”

“…In the inflammatory tumor stroma, IDO1 inhibitors block neovascularization, deprive reactive stromal CAF of IDO1 activity, and blunt the production and suppressive activity of MDSC. Preclinical studies show that IDOi potently leverage the efficacy of ‘immunogenic’ radiotherapy and chemotherapeutic drugs, including many DNA damaging drugs [30, 143]. Through these multimodal effects, IDO1 inhibitors act as immunometabolic adjuvants to empower ‘immunogenic’ therapy or frank immunotherapy approaches in otherwise weakly or non-responding tumors as noted.…”