Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity
Scott R. Walsh, Donald Bastin, Lan Chen, Andrew Nguyen, Christopher J. Storbeck, Charles Lefebvre, David Stojdl, Jonathan L. Bramson, John C. Bell, Yonghong Wan
Scott R. Walsh, Donald Bastin, Lan Chen, Andrew Nguyen, Christopher J. Storbeck, Charles Lefebvre, David Stojdl, Jonathan L. Bramson, John C. Bell, Yonghong Wan
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Research Article Autoimmunity

Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity

Abstract

Despite its success in treating melanoma and hematological malignancies, adoptive cell therapy (ACT) has had only limited effects in solid tumors. This is due in part to a lack of specific antigen targets, poor trafficking and infiltration, and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVVs) to drive expansion and tumor infiltration of transferred antigen-specific T cells and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequences when the antigen targeted was a self-protein. However, modulation of IFN-α/-β signaling, either by functional blockade or rational selection of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFN-α/-β in facilitating autoimmune toxicity during cancer immunotherapy and presents a safe and powerful combinatorial regimen with immediate translational applications.

Authors

Scott R. Walsh, Donald Bastin, Lan Chen, Andrew Nguyen, Christopher J. Storbeck, Charles Lefebvre, David Stojdl, Jonathan L. Bramson, John C. Bell, Yonghong Wan

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Figure 5

VacV-based combination therapy induces tumor regression in the absence of autoimmune diabetes.

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VacV-based combination therapy induces tumor regression in the absence o...
(A) gp33-specific CD8+ T cell responses, (B) tumor volume, and (C) survival following combination therapy in B16-gp33 tumor–bearing RIP-gp mice were measured on the indicated days after infection with VacV-gp33 (n = 4) or P14TCM cells plus VacV-gp33 (n = 5). (D) Immunohistochemical staining of pancreatic tissues from RIP-gp mice treated with P14 TCM cells plus VacV-gp33 shows maintenance of insulin-positive β cells. (E) Micrographs of pancreatic tissues stained with an anti-CD8 Ab show relative T cell infiltration of islets induced by the indicated treatments. Scale bars: 20 μm. (F) Quantification of gp33-specific CD8+ T cells using tetramer flow cytometric staining revealed no significant difference in pancreas infiltration induced by VSV or VacV vectors (n = 4). (G) Percent specific lysis of B16-gp33 or B16F10 cells by CD8+T cells isolated from mice treated with either VSV or VacV-based combination therapies (n = 5). Data for A–C represent 1 of 3 experiments and are shown as the mean ± SD. *P < 0.05 and **P < 0.01, by 2-tailed Student’s t test (A and F), log-rank (Mantel-Cox) test (C), and 1-way ANOVA with Holm-Sidak correction for multiple comparisons (G).