Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancer
Purpose: Endocrine resistance hormone receptor-positive (HR+) advanced breast cancer (ABC) is generally insensitive to immunecheckpoint inhibitors (ICIs). This study sought to determine whether PI3Kδ inhibitor could enhance the sensitivity of endocrine resistance HR + advanced BC to ICIs by reducing...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844023057067 |
| _version_ | 1797733014027894784 |
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| author | Yingjue Li Yiwen Li Yu Yang Yuwei Deng Xiangdong Ni Bochen Zhao Zhaoqi Yan Wen He Yixin Li Shuhui Li Linbo Liu Dan Lu |
| author_facet | Yingjue Li Yiwen Li Yu Yang Yuwei Deng Xiangdong Ni Bochen Zhao Zhaoqi Yan Wen He Yixin Li Shuhui Li Linbo Liu Dan Lu |
| author_sort | Yingjue Li |
| collection | DOAJ |
| description | Purpose: Endocrine resistance hormone receptor-positive (HR+) advanced breast cancer (ABC) is generally insensitive to immunecheckpoint inhibitors (ICIs). This study sought to determine whether PI3Kδ inhibitor could enhance the sensitivity of endocrine resistance HR + advanced BC to ICIs by reducing immune evasion. Methods: Patient-derived HR + ABC xenografts were implanted into immune-humanized NSG mice and subsequently treated with YY20394 (PI3Kδ inhibitor) and camrelizumab. The mice were monitored for tumor progression, biochemical blood indicators, and peripheral blood T-cell subsets. The xenografted tumors were collected at the end of the treatment cycle and subjected to HE staining, immunohistochemistry and protein phosphorylation analysis. Besides, the xenografted tumors were also used to isolate primary breast cancer cells (BCCs) and regulatory T-cells (Tregs), which were subsequently used to evaluate drug sensitivity in vitro. Results: The humanized PDX model showed a favorable initial treatment response to camrelizumab combined with YY20394 and manageable toxicity. YY20394 plus camrelizumab showed a strong inhibitory effect on HR + BC in vivo mediated by suppression of Treg activity and an increased proportion of CD8+ T cells. Mice bearing tumors treated with YY20394 and camrelizumab had less invasion, mitotic figures, and ki67 expression, while having higher IL-12 expression compared with other groups. Mechanistically, YY20394 only effectively inhibited the PI3K pathway and proliferation activity in Tregs but not in BCCs. Conclusion: Our study suggests PI3Kδ inhibitor could the enhance the efficacy of ICIs in HR + BC PDX models by combating immune suppression and provides a feasible approach that may overcome the resistance of ICIs in HR + BC patients. |
| first_indexed | 2024-03-12T12:22:56Z |
| format | Article |
| id | doaj.art-b1ed9577c185450f955ac95c6e7c9986 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-03-12T12:22:56Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-b1ed9577c185450f955ac95c6e7c99862023-08-30T05:51:32ZengElsevierHeliyon2405-84402023-08-0198e18498Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancerYingjue Li0Yiwen Li1Yu Yang2Yuwei Deng3Xiangdong Ni4Bochen Zhao5Zhaoqi Yan6Wen He7Yixin Li8Shuhui Li9Linbo Liu10Dan Lu11Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, PR ChinaDepartment of Oncology, The Second Affiliated Hospital of Harbin Medical University, PR ChinaDepartment of Oncology, The Second Affiliated Hospital of Harbin Medical University, PR ChinaDepartment of Oncology, Affiliated Oncology Hospital of Harbin Medical University, PR ChinaDepartment of Oncology, Hegang People's Hospital, PR ChinaDepartment of Oncology, General Hospital of Shenzhen University, PR ChinaDepartment of Breast Surgery, The Second Affiliated Hospital of Harbin Medical University, PR ChinaDepartment of Oncology, The Second Affiliated Hospital of Harbin Medical University, PR ChinaDepartment of Oncology, Second Affiliated Hospital of Medical College of Shantou University, PR ChinaDepartment of Oncology, The Second Affiliated Hospital of Harbin Medical University, PR ChinaDepartment of Oncology, The Second Affiliated Hospital of Harbin Medical University, PR ChinaDepartment of Oncology, The Second Affiliated Hospital of Harbin Medical University, PR China; Corresponding author. Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin City, Heilongjiang Province, PR China.Purpose: Endocrine resistance hormone receptor-positive (HR+) advanced breast cancer (ABC) is generally insensitive to immunecheckpoint inhibitors (ICIs). This study sought to determine whether PI3Kδ inhibitor could enhance the sensitivity of endocrine resistance HR + advanced BC to ICIs by reducing immune evasion. Methods: Patient-derived HR + ABC xenografts were implanted into immune-humanized NSG mice and subsequently treated with YY20394 (PI3Kδ inhibitor) and camrelizumab. The mice were monitored for tumor progression, biochemical blood indicators, and peripheral blood T-cell subsets. The xenografted tumors were collected at the end of the treatment cycle and subjected to HE staining, immunohistochemistry and protein phosphorylation analysis. Besides, the xenografted tumors were also used to isolate primary breast cancer cells (BCCs) and regulatory T-cells (Tregs), which were subsequently used to evaluate drug sensitivity in vitro. Results: The humanized PDX model showed a favorable initial treatment response to camrelizumab combined with YY20394 and manageable toxicity. YY20394 plus camrelizumab showed a strong inhibitory effect on HR + BC in vivo mediated by suppression of Treg activity and an increased proportion of CD8+ T cells. Mice bearing tumors treated with YY20394 and camrelizumab had less invasion, mitotic figures, and ki67 expression, while having higher IL-12 expression compared with other groups. Mechanistically, YY20394 only effectively inhibited the PI3K pathway and proliferation activity in Tregs but not in BCCs. Conclusion: Our study suggests PI3Kδ inhibitor could the enhance the efficacy of ICIs in HR + BC PDX models by combating immune suppression and provides a feasible approach that may overcome the resistance of ICIs in HR + BC patients.http://www.sciencedirect.com/science/article/pii/S2405844023057067Breast cancer (BC)Patient-derived xenograftImmune checkpoint inhibitorsPI3Kδ inhibitorEndocrine therapy resistanceHumanized mice |
| spellingShingle | Yingjue Li Yiwen Li Yu Yang Yuwei Deng Xiangdong Ni Bochen Zhao Zhaoqi Yan Wen He Yixin Li Shuhui Li Linbo Liu Dan Lu Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancer Heliyon Breast cancer (BC) Patient-derived xenograft Immune checkpoint inhibitors PI3Kδ inhibitor Endocrine therapy resistance Humanized mice |
| title | Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancer |
| title_full | Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancer |
| title_fullStr | Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancer |
| title_full_unstemmed | Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancer |
| title_short | Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancer |
| title_sort | synergistic efficacy of pi3kδ inhibitor with anti pd 1 mabs in immune humanized pdx model of endocrine resistance hormone receptor positive advanced breast cancer |
| topic | Breast cancer (BC) Patient-derived xenograft Immune checkpoint inhibitors PI3Kδ inhibitor Endocrine therapy resistance Humanized mice |
| url | http://www.sciencedirect.com/science/article/pii/S2405844023057067 |
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