Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer
Treatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20%...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/12/3089 |
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| author | Roukiah Khalil Ryan J. Green Kavya Sivakumar Payal Varandani Srinivas Bharadwaj Shyam S. Mohapatra Subhra Mohapatra |
| author_facet | Roukiah Khalil Ryan J. Green Kavya Sivakumar Payal Varandani Srinivas Bharadwaj Shyam S. Mohapatra Subhra Mohapatra |
| author_sort | Roukiah Khalil |
| collection | DOAJ |
| description | Treatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20% of patients due to immune resistance. Therefore, synergistic combinatorial approaches that overcome immune resistance are currently under investigation. Herein, we studied the immunomodulatory role of Withaferin A (WFA)—a herbal compound—and its effectiveness in combination with an ICB for the treatment of NSCLC. Our in vitro results show that WFA induces immunogenic cell death (ICD) in NSCLC cell lines and increases expression of the programmed death ligand-1 (PD-L1). The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process. Further, we found that a combination of WFA and α-PD-L1 significantly reduced tumor growth in an immunocompetent tumor model. Our results showed that WFA increases CD-8 T-cells and reduces immunosuppressive cells infiltrating the tumor microenvironment. Administration of NAC partially inhibited the anti-tumor response of the combination regimen. In conclusion, our results demonstrate that WFA sensitizes NSCLC to α-PD-L1 in part via activation of ROS. |
| first_indexed | 2024-03-09T10:58:14Z |
| format | Article |
| id | doaj.art-699d4cd775b9429f90dc396e1e5be62f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T10:58:14Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-699d4cd775b9429f90dc396e1e5be62f2023-12-01T01:29:34ZengMDPI AGCancers2072-66942023-06-011512308910.3390/cancers15123089Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung CancerRoukiah Khalil0Ryan J. Green1Kavya Sivakumar2Payal Varandani3Srinivas Bharadwaj4Shyam S. Mohapatra5Subhra Mohapatra6Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USATaneja School of Pharmacy, University of South Florida, Tampa, FL 33612, USADepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USATreatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20% of patients due to immune resistance. Therefore, synergistic combinatorial approaches that overcome immune resistance are currently under investigation. Herein, we studied the immunomodulatory role of Withaferin A (WFA)—a herbal compound—and its effectiveness in combination with an ICB for the treatment of NSCLC. Our in vitro results show that WFA induces immunogenic cell death (ICD) in NSCLC cell lines and increases expression of the programmed death ligand-1 (PD-L1). The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process. Further, we found that a combination of WFA and α-PD-L1 significantly reduced tumor growth in an immunocompetent tumor model. Our results showed that WFA increases CD-8 T-cells and reduces immunosuppressive cells infiltrating the tumor microenvironment. Administration of NAC partially inhibited the anti-tumor response of the combination regimen. In conclusion, our results demonstrate that WFA sensitizes NSCLC to α-PD-L1 in part via activation of ROS.https://www.mdpi.com/2072-6694/15/12/3089PD-L1immune checkpoint blockersimmunotherapyWithaferin Acombination therapylung cancer |
| spellingShingle | Roukiah Khalil Ryan J. Green Kavya Sivakumar Payal Varandani Srinivas Bharadwaj Shyam S. Mohapatra Subhra Mohapatra Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer Cancers PD-L1 immune checkpoint blockers immunotherapy Withaferin A combination therapy lung cancer |
| title | Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer |
| title_full | Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer |
| title_fullStr | Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer |
| title_full_unstemmed | Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer |
| title_short | Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer |
| title_sort | withaferin a increases the effectiveness of immune checkpoint blocker for the treatment of non small cell lung cancer |
| topic | PD-L1 immune checkpoint blockers immunotherapy Withaferin A combination therapy lung cancer |
| url | https://www.mdpi.com/2072-6694/15/12/3089 |
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