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Effect of Incomplete Cryoablation and Matrix Metalloproteinase Inhibition on Intratumoral CD8+ T-Cell Infiltration in Murine Hepatocellular …

A Shewarega, JG Santana, D Nam, A Berz, J Tefera… - Radiology, 2024 - pubs.rsna.org
A Shewarega, JG Santana, D Nam, A Berz, J Tefera, V Kahl, SK Mishra, D Coman, J Duncan
Radiology, 2024pubs.rsna.org
137 天前 - Background Image-guided tumor ablation is the first-line therapy for early-stage
hepatocellular carcinoma (HCC), with ongoing investigations into its combination with
immunotherapies. Matrix metalloproteinase (MMP) inhibition demonstrates
immunomodulatory potential and reduces HCC tumor growth when combined with ablative
treatment. Purpose To evaluate the effect of incomplete cryoablation with or without MMP
inhibition on the local immune response in residual tumors in a murine HCC model …
Background
Image-guided tumor ablation is the first-line therapy for early-stage hepatocellular carcinoma (HCC), with ongoing investigations into its combination with immunotherapies. Matrix metalloproteinase (MMP) inhibition demonstrates immunomodulatory potential and reduces HCC tumor growth when combined with ablative treatment.
Purpose
To evaluate the effect of incomplete cryoablation with or without MMP inhibition on the local immune response in residual tumors in a murine HCC model.
Materials and Methods
Sixty 8- to 10-week-old female BALB/c mice underwent HCC induction with use of orthotopic implantation of syngeneic Tib-75 cells. After 7 days, mice with a single lesion were randomized into treatment groups: (a) no treatment, (b) MMP inhibitor, (c) incomplete cryoablation, and (d) incomplete cryoablation and MMP inhibitor. Macrophage and T-cell subsets were assessed in tissue samples with use of immunohistochemistry and immunofluorescence (cell averages calculated using five 1-μm2 fields of view [FOVs]). C-X-C motif chemokine receptor type 3 (CXCR3)– and interferon γ (IFNγ)–positive T cells were assessed using flow cytometry. Groups were compared using unpaired Student t tests, one-way analysis of variance with Tukey correction, and the Kruskal-Wallis test with Dunn correction.
Results
Mice treated with incomplete cryoablation (n = 6) showed greater infiltration of CD206+ tumor-associated macrophages (mean, 1.52 cells per FOV vs 0.64 cells per FOV; P = .03) and MMP9-expressing cells (mean, 0.89 cells per FOV vs 0.11 cells per FOV; P = .03) compared with untreated controls (n = 6). Incomplete cryoablation with MMP inhibition (n = 6) versus without (n = 6) led to greater CD8+ T-cell (mean, 15.8% vs 8.29%; P = .04), CXCR3+CD8+ T-cell (mean, 11.64% vs 8.47%; P = .004), and IFNγ+CD8+ T-cell infiltration (mean, 11.58% vs 5.18%; P = .02).
Conclusion
In a mouse model of HCC, incomplete cryoablation and systemic MMP inhibition showed increased cytotoxic CD8+ T-cell infiltration into the residual tumor compared with either treatment alone.
© RSNA, 2024
See also the editorial by Gemmete in this issue.
Radiological Society of North America