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Background <p>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.</p> Methods <p>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 −&#xa0;150, −&#xa0;150 to −&#xa0;300, −&#xa0;300 to –&#xa0;450&#xa0;μm). High endothelial venule (HEV) formation was evaluated via CD31/MECA79 dual immunofluorescence.</p> Results <p>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, <i>p</i> = 0.04) and triple combination therapy (1.7-fold reduction, <i>p</i> = 0.03). In MC38, at −&#xa0;150 to −&#xa0;300&#xa0;μm, anti-PD-L1 + anti-VEGF enhanced CD8 + Granzyme B + cells 1.9-fold versus Control (<i>p</i> = 0.01). In HM-1, at 0 to −&#xa0;150&#xa0;μm, triple therapy enhanced CD8 + Granzyme B + cells 2.8-fold (<i>p</i> = 0.02), while anti-PD-L1 + anti-VEGF increased CD8 + Granzyme B + cells 2.5-fold (<i>p</i> = 0.03). Both triple and anti-PD-L1 + anti-VEGF therapies induced CD31 + MECA79 + HEV formation (<i>p</i> &lt; 0.01).</p> Conclusions <p>Triple therapy may overcome immune-desert ovarian cancer through additive HEV formation, enhancing cytotoxic CD8 + T cell infiltration into the tumor.</p>

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Digital spatial profiling reveals additive effects of triple therapy on tumor microenvironment: anti-PD-L1, anti-VEGF, and PARP inhibition in mouse models

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  • 发表日期：

    2026年2月7日

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  • Akihiko Ueda,
  • Ryusuke Murakami,
  • Kentaro Ishida,
  • Kohei Hamada,
  • Jumpei Ogura,
  • Shunsuke Kawahara,
  • Yuka Mise,
  • Yuko Hosoe,
  • Masamichi Sugimoto,
  • Daiko Wakita,
  • Taito Miyamoto,
  • Rin Mizuno,
  • Mana Taki,
  • Koji Yamanoi,
  • Ken Yamaguchi,
  • Junzo Hamanishi,
  • Masaki Mandai

摘要

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.