Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model
Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infilt...
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| Format: | Article |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.632364/full |
| _version_ | 1818662485733933056 |
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| author | Tianyun Qiao Yanlu Xiong Yangbo Feng Wenwen Guo Yongsheng Zhou Jinbo Zhao Tao Jiang Changhong Shi Yong Han Yong Han |
| author_facet | Tianyun Qiao Yanlu Xiong Yangbo Feng Wenwen Guo Yongsheng Zhou Jinbo Zhao Tao Jiang Changhong Shi Yong Han Yong Han |
| author_sort | Tianyun Qiao |
| collection | DOAJ |
| description | Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC. |
| first_indexed | 2024-12-17T05:01:42Z |
| format | Article |
| id | doaj.art-27738725f5db451e9bbac647d9284625 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-17T05:01:42Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-27738725f5db451e9bbac647d92846252022-12-21T22:02:32ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-03-011110.3389/fonc.2021.632364632364Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse ModelTianyun Qiao0Yanlu Xiong1Yangbo Feng2Wenwen Guo3Yongsheng Zhou4Jinbo Zhao5Tao Jiang6Changhong Shi7Yong Han8Yong Han9Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, ChinaSchool of Basic Medical Sciences, Medical College of Yan’an University, Yanan, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, ChinaLaboratory Animal Center, The Fourth Military Medical University, Xi’an, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, ChinaDepartment of Thoracic Surgery, Air Force Medical Center, Beijing, ChinaImmunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.https://www.frontiersin.org/articles/10.3389/fonc.2021.632364/fullnon-small cell lung cancerNSCLCimmunotherapyanti-PD-1oxamateLDH |
| spellingShingle | Tianyun Qiao Yanlu Xiong Yangbo Feng Wenwen Guo Yongsheng Zhou Jinbo Zhao Tao Jiang Changhong Shi Yong Han Yong Han Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model Frontiers in Oncology non-small cell lung cancer NSCLC immunotherapy anti-PD-1 oxamate LDH |
| title | Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model |
| title_full | Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model |
| title_fullStr | Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model |
| title_full_unstemmed | Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model |
| title_short | Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model |
| title_sort | inhibition of ldh a by oxamate enhances the efficacy of anti pd 1 treatment in an nsclc humanized mouse model |
| topic | non-small cell lung cancer NSCLC immunotherapy anti-PD-1 oxamate LDH |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.632364/full |
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