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 3

STING agonist 8803 induces immune effector responses within gliomas.

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STING agonist 8803 induces immune effector responses within gliomas. Flo...
Flow cytometric analysis of QPP8-infiltrating immune cells using BD LSRFortessa X-30 prototype flow cytometer. QPP8 cells were orthotopically implanted into C57BL/6J mice and then treated with PBS or 5 μg 8803 on days 60 and 67. Tumors were isolated 48 hours after the final treatment, and immune cells were collected using a Percoll gradient. (A) Within the CD8+ T cell compartment from the tumor and cervical lymph nodes (LNs), 8803 enhanced the number of infiltrating CD8+ T cells. (B) CD8+ T cell immune exhaustion markers such as PD-1 and LAG-3 were decreased, but proliferation and granzyme B expression increased. (C) NK cell infiltration and frequency and granzyme B expression were increased in 8803-treated gliomas. (D) The survival rate estimated by the Kaplan-Meier method of RAG–/– versus WT C57BL/6J mice implanted with QPP8v (subclone) and treated with STING agonist 8803 versus PBS. RAG–/– control (PBS): 5 mice (median survival [MS]: 63 days); WT control: 5 mice (MS: 76 days); RAG–/– 8803: 5 mice (MS: 55 days); WT 8803: 5 mice (MS: undefined; 3 long-term survivors). Statistics (log-rank test): RAG–/– control versus WT control P = 0.209; RAG–/– control versus RAG–/– 8803 P = 0.192; RAG–/– control versus WT 8803 P = 0.0018; RAG–/– 8803 versus WT 8803 P = 0.0018; RAG–/– 8803 versus WT control P = 0.014; WT control versus WT 8803 P = 0.0018. (E) The survival estimated by the Kaplan-Meier method of C57BL/6J mice implanted with QPP8v and treated with either 8803 or the combination of 8803 + NK1.1 antibody (αNK1.1). Control (PBS): 5 mice (MS: 34 days); 8803: 5 mice (MS: 76 days); 8803 + αNK1.1: 5 mice (MS: 79 days). Statistics (log-rank test): control versus 8803 P = 0.0017; control versus 8803 + αNK1.1 P = 0.0062; 8803 versus 8803 + αNK1.1 P = 0.92. (F) Expansion of OT-1 CD8+ T cells or WT CD8+ T cells collected from spleen and then treated with PBS versus 8803 at 1, 5, and 10 μM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 2-tailed Student’s t test (A–C) or 2-way ANOVA (F).