Laser Interstitial Thermal Therapy (LITT) Remodels the Tumor Immune Landscape and Prolongs Survival in a Mouse Glioma Model

Introduction: Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique for tumor ablation. It is increasingly being used in clinical practice to treat primary and recurrent glioma, but little is known about the impact of LITT on the tumor microenvironment and immune response. We developed a mouse model of LITT and applied it to a poorly immunogenic mouse model of glioma.

Methods: SB28 glioma cells were implanted in the right frontal lobe of C57BL/6 mice, and on day 7, an optical fiber was inserted into the tumor, paired with a thermocouple for real-time temperature monitoring. A current was applied to maintain a peri-lesional temperature of 44C for 90 seconds at two depths. The tumor and associated immune response was analyzed by MRI, multiparameter flow cytometry, single cell RNA-seq, spatial transcriptomics, and multiplex immunofluorescence. Clinical outcomes were determined by assessment for neurologic deficits.

Results: LITT created a lesion with contrast-enhancement and edema, similar to that observed clinically. There was a significant increase in neutrophils in the acute infiltrate (3 days post treatment) while select adaptive immune cell populations including type 1 conventional dendritic cells, NK cells, and gamma delta T cells were enriched in the subacute period (7 days post treatment). Overall, however, the dominant population was monocytes/macrophages, and scRNA-seq revealed particular enrichment of a Fabp5- and Gpnmb-expressing macrophage subset following LITT. Multiplex immunofluorescence and spatial transcriptomics further identified the regional distribution of these subsets. Finally, laser ablation prolonged survival compared to sham surgery.

Conclusion : LITT modifies the tumor immune infiltrate with increases in neutrophils as well as select adaptive cell and macrophage subsets. This correlates with prolonged survival in a poorly immunogenic glioma model. Our mouse model of LITT offers a clinically-relevant tool for generation of novel treatment strategies with potential for rapid clinical translation.