論文 - 詳細
| RRC ID | 86747 |
|---|---|
| 著者 | Ueda A, Murakami R, Ishida K, Hamada K, Ogura J, Kawahara S, Mise Y, Hosoe Y, Sugimoto M, Wakita D, Miyamoto T, Mizuno R, Taki M, Yamanoi K, Yamaguchi K, Hamanishi J, Mandai M. |
| タイトル | Digital spatial profiling reveals additive effects of triple therapy on tumor microenvironment: anti-PD-L1, anti-VEGF, and PARP inhibition in mouse models. |
| ジャーナル | Cancer Immunol Immunother |
| Abstract |
BACKGROUND:Immune checkpoint inhibitors show limited efficacy against immune-desert tumors, including ovarian cancer. We investigated triple therapy combining anti-programmed cell death-ligand 1 (PD-L1) antibody, anti-vascular endothelial growth factor (VEGF) antibody, and Poly ADP-ribose polymerase inhibitor (PARPi) on tumor microenvironment using spatial profiling. METHODS:Two mouse models were employed: MC38 (immune-inflamed phenotype) and HM-1 (immune-desert phenotype). MC38 mice received anti-PD-L1 and anti-VEGF as monotherapy or dual combination. HM-1 mice received anti-PD-L1, anti-VEGF, and PARPi as monotherapy, dual combinations (anti-PD-L1 + anti-VEGF, anti-PD-L1 + PARPi, anti-VEGF + PARPi), or triple combination (anti-PD-L1 + anti-VEGF + PARPi). Spatial distribution of immune cells and the tumor microenvironment was analyzed using immunohistochemistry (CD8) and dual immunofluorescence (CD8/Granzyme B) with distance-based density quantification from tumor margins (0 to - 150, - 150 to - 300, - 300 to - 450 μm). High endothelial venule (HEV) formation was evaluated via CD31/MECA79 dual immunofluorescence. RESULTS:MC38 tumors responded to all treatments by day 10. Conversely, HM-1 tumors showed no response at day 10 but responded to two combination therapies by day 20: anti-PD-L1 + anti-VEGF (1.5-fold reduction, p = 0.04) and triple combination therapy (1.7-fold reduction, p = 0.03). In MC38, at - 150 to - 300 μm, anti-PD-L1 + anti-VEGF enhanced CD8 + Granzyme B + cells 1.9-fold versus Control (p = 0.01). In HM-1, at 0 to - 150 μm, triple therapy enhanced CD8 + Granzyme B + cells 2.8-fold (p = 0.02), while anti-PD-L1 + anti-VEGF increased CD8 + Granzyme B + cells 2.5-fold (p = 0.03). Both triple and anti-PD-L1 + anti-VEGF therapies induced CD31 + MECA79 + HEV formation (p < 0.01). CONCLUSIONS:Triple therapy may overcome immune-desert ovarian cancer through additive HEV formation, enhancing cytotoxic CD8 + T cell infiltration into the tumor. |
| 巻・号 | 75(3) |
| ページ | 70 |
| 公開日 | 2026-2-7 |
| DOI | 10.1007/s00262-026-04312-3 |
| PII | 10.1007/s00262-026-04312-3 |
| PMID | 41653296 |
| PMC | PMC12882906 |
| MeSH | Animals Antineoplastic Combined Chemotherapy Protocols* / pharmacology Antineoplastic Combined Chemotherapy Protocols* / therapeutic use B7-H1 Antigen* / antagonists & inhibitors B7-H1 Antigen* / immunology Cell Line, Tumor Disease Models, Animal Female Humans Immune Checkpoint Inhibitors* / pharmacology Mice Ovarian Neoplasms / drug therapy Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology Poly(ADP-ribose) Polymerase Inhibitors* / therapeutic use Tumor Microenvironment* / drug effects Tumor Microenvironment* / immunology Vascular Endothelial Growth Factor A* / antagonists & inhibitors Vascular Endothelial Growth Factor A* / immunology |
| IF | 5.442 |
| リソース情報 | |
| ヒト・動物細胞 | OV2944-HM-1(RCB1483) |