STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma
Hinda Najem, … , Michael A. Curran, Amy B. Heimberger
Hinda Najem, … , Michael A. Curran, Amy B. Heimberger
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(12):e175033. https://doi.org/10.1172/JCI175033.
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Research Article Immunology Oncology

STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma

Abstract

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade–resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti–PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade–responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.

Authors

Hinda Najem, Spencer T. Lea, Shashwat Tripathi, Lisa Hurley, Chao-Hsien Chen, Ivana William, Moloud Sooreshjani, Michelle Bowie, Genevieve Hartley, Corey Dussold, Sebastian Pacheco, Crismita Dmello, Catalina Lee-Chang, Kathleen McCortney, Alicia Steffens, Jordain Walshon, Martina Ott, Jun Wei, Anantha Marisetty, Irina Balyasnikova, Roger Stupp, Rimas V. Lukas, Jian Hu, Charles David James, Craig M. Horbinski, Maciej S. Lesniak, David M. Ashley, Waldemar Priebe, Leonidas C. Platanias, Michael A. Curran, Amy B. Heimberger

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Figure 1

The prognostic impact and localization of the STING pathway in human glioblastoma.

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The prognostic impact and localization of the STING pathway in human gli...
(A) Kaplan-Meier survival curves of newly diagnosed IDH-1–WT glioblastoma patients stratified based on high versus low expression stratified on the median of the designated marker. STING (TMEM173): high (n = 71, events = 62; median = 12.6); low (n = 71, events = 54, median = 13.8); HR = 1 (0.69–1.45); log-rank P value = 0.99; Wilcoxon’s P value = 0.92. IRF3: high (n = 71; events = 62; median = 11.2); low (n = 71, events = 54; median = 14.7); HR = 0.84 (0.58–1.22); log-rank P value = 0.37; Wilcoxon’s P value = 0.08. Tbk1: high (n = 72, events = 57, median = 12.9); low (n = 70, events = 59, median = 13.8); HR = 0.74 (0.51–1.08); log-rank P value = 0.12; Wilcoxon’s P value = 0.67. STAT3: high (n = 72, events = 57, median = 11.8); low (n = 70, events = 59, median = 13.8); HR = 0.74 (0.51–1.08); log-rank P value = 0.11; Wilcoxon’s P value = 0.23. PD-1 (PDCD1): high (n = 72, events = 57, median = 12.3); low (n = 70, events = 59, median = 13.8); HR = 0.94 (0.65–1.36); log-rank P value = 0.76; Wilcoxon’s P value = 0.72. (B) RNA sequencing data from the Ivy Glioblastoma Atlas project was analyzed based on differences in the anatomical locations of these markers in primary gliomas. The y axes show z score–normalized mRNA expression. LE, leading edge; IT, infiltrating tumor; CT, cellular tumor; PZ, perinecrotic zone; PS, pseudopalisading cells around necrosis; HPV, hyperplastic blood vessels in cellular tumor; MP, microvascular proliferation. (C) Representative multiplexed sequential immunofluorescence (SeqIF) imaging of human glioblastoma showing the transition of the microenvironment from tumor to brain, with the highest expression of perivascular STING at the edge. Color panel: DAPI, dark blue; CD31, cyan blue; GFAP, blue; and STING, red. Scale bar: 500 μm. (D) Representative multiplexed SeqIF imaging of human glioblastoma, demonstrating the confinement of T cells to the perivascular regions of CD31+ vessels, as described and quantified in the spatial bioinformatic analysis protocol by Najem et al. (57). Color panel: DAPI, dark blue; CD31, cyan blue; GFAP, blue; STING, red; CD4, yellow; and CD8, white. Yellow arrows indicate CD4+ T cells and white arrows indicate CD8+ T cells. Scale bar: 100 μm. (E) Analysis of mRNA STING expression in non–tumor-bearing brain relative to high-grade glioma (HGG) (27). Box-and-whisker plots show the minimum and maximum; lines represent 25%, median, and 75%. For non-tumor, min: 5.936, max: 7.743, 25%: 6.113, 75%: 7.083, median: 6.753. For HGG, min: 6.715, max: 8.158, 25%: 7.451, 75%: 8.229, median: 7.668. ****P < 0.0001 (2-tailed Student’s t test).