Intratumoral IL-12 delivery via mesenchymal stem cells combined with PD-1 blockade leads to long-term antitumor immunity in a mouse glioblastoma model - 22/03/24
Abstract |
Background |
Although PD-1 blockade is effective for treating several types of cancer, the efficacy of this agent in glioblastoma is largely limited. To overcome non-responders and the immunosuppressive tumor microenvironment, combinational immunotherapeutic strategies with anti-PD-1 need to be considered. Here, we developed IL-12-secreting mesenchymal stem cells (MSC_IL-12) with glioblastoma tropism and evaluated the therapeutic effects of anti-PD-1, MSC_IL-12, and their combination against glioblastoma.
Methods |
Therapeutic responses were evaluated using an immunocompetent mouse orthotopic model. Tumor-infiltrating lymphocytes (TILs) were analyzed using immunofluorescent imaging. Single-cell transcriptome was obtained from mouse brains after treatments.
Results |
Anti-PD-1 and MSC_IL-12 showed complete tumor remission in 25.0% (4/16) and 23.1% (3/13) of glioblastoma-implanted mice, respectively, and their combination yielded synergistic antitumor efficacy indicated by 50.0% (6/12) of complete tumor remission. Analyses of TILs revealed that anti-PD-1 increased CD8+ T cells, while MSC_IL-12 led to infiltration of CD4+ T cells and NK cells. Both therapies reduced frequencies of Tregs. All these aspects observed in each monotherapy group were superimposed in the combination group. Notably, no tumor growth was observed upon rechallenge in cured mice, indicating long-term immunity against glioblastoma provoked by the therapies. Single-cell RNA-seq data confirmed these results and revealed that the combined treatment led to immune-favorable tumor microenvironment–CD4+, CD8+ T cells, effector memory T cells, and activated microglia were increased, whereas exhausted T cells, Tregs, and M2 polarized microglia were reduced.
Conclusion |
Anti-PD-1 and MSC_IL-12 monotherapies show long-term therapeutic responses, and their combination further enhances antitumor efficacy against glioblastoma via inducing immune-favorable tumor microenvironment.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | MSC_IL-12 has pathotropism to glioblastoma with long-term secretion of IL-12. |
• | Combined treatment with MSC_IL-12 and anti-PD-1 suppresses glioblastoma. |
• | Anti-PD-1 increases CD8+ T cells and MSC_IL-12 augments CD4+ T cells and NK cells. |
• | Combined anti-PD-1 and MSC_IL-12 treatment leads immune-favorable microenvironment. |
• | Combined anti-PD-1 and MSC_IL-12 evokes long-term immunity against glioblastoma. |
Abbreviations : Ad-IL-12, ICI, MSC_IL-12, scRNA-seq, Treg cell, TUNEL
Keywords : Cancer immunotherapy, IL-12, Long-term immunity, Mesenchymal stem cell, PD-1, Single cell RNA-seq
Plan
Vol 173
Article 115790- avril 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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