Imaging activated T cells predicts response to cancer vaccines
Israt S. Alam, … , Ronald Levy, Sanjiv S. Gambhir
Israt S. Alam, … , Ronald Levy, Sanjiv S. Gambhir
Published March 29, 2018
Citation Information: J Clin Invest. 2018;128(6):2569-2580. https://doi.org/10.1172/JCI98509.
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Research Article Immunology Oncology Article has an altmetric score of 39

Imaging activated T cells predicts response to cancer vaccines

Abstract

In situ cancer vaccines are under active clinical investigation, given their reported ability to eradicate both local and disseminated malignancies. Intratumoral vaccine administration is thought to activate a T cell–mediated immune response, which begins in the treated tumor and cascades systemically. In this study, we describe a PET tracer (64Cu-DOTA-AbOX40) that enabled noninvasive and longitudinal imaging of OX40, a cell-surface marker of T cell activation. We report the spatiotemporal dynamics of T cell activation following in situ vaccination with CpG oligodeoxynucleotide in a dual tumor–bearing mouse model. We demonstrate that OX40 imaging was able to predict tumor responses on day 9 after treatment on the basis of tumor tracer uptake on day 2, with greater accuracy than both anatomical and blood-based measurements. These studies provide key insights into global T cell activation following local CpG treatment and indicate that 64Cu-DOTA-AbOX40 is a promising candidate for monitoring clinical cancer immunotherapy strategies.

Authors

Israt S. Alam, Aaron T. Mayer, Idit Sagiv-Barfi, Kezheng Wang, Ophir Vermesh, Debra K. Czerwinski, Emily M. Johnson, Michelle L. James, Ronald Levy, Sanjiv S. Gambhir

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Figure 2

In situ vaccination with CpG activates OX40+ T cells in the local tumor and TDLNs, leading to the onset of a systemic response.

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In situ vaccination with CpG activates OX40+ T cells in the local tumor ...
(A) Schematic representation of the in situ vaccination strategy and a hypothetical immune response. (B) Treated tumor (TT) and untreated tumor (UT) growth curves (volume, mm3) based on caliper measurements for CpG-treated (n = 7) and vehicle-treated (n = 8) cohorts. Values represent the mean ± SEM. ****P < 0.0001 and **P < 0.01, by 2-way ANOVA with Bonferroni’s post test. (C) Top: Fold change (normalized to vehicle) in the frequency of OX40+CD3+ T cells in CpG-treated versus untreated TDLNs and (D) tumors at early (n = 5 mice/group) and late (n = 4 mice/group) time points. Bottom: Fold change in the frequency of CD3+ T cells. Gray dashed line demarcates unity. Values represent the mean ± SEM. Statistical analysis was performed using a 2-way ANOVA. P values represent probability differences over time in marker expression due to random chance. (E) Representative viSNE clustering of CD4+, CD8+, and OX40+ markers at the early time point in the CpG-treated cohort. (F) Images of spleens (late time point) from CpG- and vehicle-treated cohorts, presented side by side. Graph shows the fold change (normalized to vehicle) in the frequency of OX40+CD3+ T cells in the CpG-treated cohort at early (n = 5 mice) and late (n = 4 mice) time points. ***P < 0.001, by unpaired Student’s t test. (G) Heatmap of log2 fold change (normalized to control mice) of cytokine expression at both early and late time points in vehicle- and CpG-treated cohorts. Columns represent mice; rows represent cytokines. Scale bars: blue = 0, yellow >4 log2 fold change.