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Using 22C3 Anti-PD-L1 Antibody Concentrate on Biopsy and Cytology Samples from Non-small Cell Lung Cancer Patients
Published on: September 25, 2018
Digital spatial profiling reveals additive effects of triple therapy on tumor microenvironment: anti-PD-L1,
Akihiko Ueda1, Ryusuke Murakami2, Kentaro Ishida1
1Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan.
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.
Insights
Triple therapy combining anti-PD-L1, anti-VEGF, and PARPi shows promise for immune-desert ovarian cancer. This approach enhances cytotoxic T cell infiltration by promoting high endothelial venule formation, potentially overcoming treatment resistance.
Area of Science:
- Immunology
- Oncology
- Cancer Therapy
Background:
- Immune checkpoint inhibitors have limited efficacy in immune-desert tumors like ovarian cancer.
- Investigating novel therapeutic strategies is crucial for improving treatment outcomes.
Purpose of the Study:
- To evaluate the efficacy of a triple therapy combination (anti-PD-L1, anti-VEGF, PARPi) in overcoming immune-desert tumors.
- To analyze the impact of this triple therapy on the tumor microenvironment using spatial profiling.
Main Methods:
- Utilized two mouse models: MC38 (immune-inflamed) and HM-1 (immune-desert).
- Administered anti-PD-L1, anti-VEGF, and PARPi as monotherapy, dual, or triple combinations.
- Assessed immune cell distribution and tumor microenvironment using immunohistochemistry and immunofluorescence, including HEV formation analysis.
Main Results:
- HM-1 tumors, resistant to single agents, responded to dual (anti-PD-L1 + anti-VEGF) and triple therapies by day 20.
- Triple therapy and anti-PD-L1 + anti-VEGF significantly increased cytotoxic CD8+ Granzyme B+ cells in HM-1 tumors.
- Both effective therapies induced high endothelial venule (HEV) formation.
Conclusions:
- Triple therapy may overcome immune-desert ovarian cancer by enhancing cytotoxic T cell infiltration.
- Additive HEV formation is a key mechanism by which triple therapy improves anti-tumor immunity.
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