Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma
Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients. We have recently reported that programmed cell death protein-1 (PD-1) ligand (PD-L1) expression is regulated by lactate present at high levels in the tumor microenvironment (TME)....
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-03-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/11/4/450 |
| _version_ | 1797710040695570432 |
|---|---|
| author | Saeed Daneshmandi Barbara Wegiel Pankaj Seth |
| author_facet | Saeed Daneshmandi Barbara Wegiel Pankaj Seth |
| author_sort | Saeed Daneshmandi |
| collection | DOAJ |
| description | Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients. We have recently reported that programmed cell death protein-1 (PD-1) ligand (PD-L1) expression is regulated by lactate present at high levels in the tumor microenvironment (TME). We hypothesized that the efficacy of anti-PD-1 treatment can be improved by blocking the lactate-generating enzyme, lactate dehydrogenase-A (LDH-A). Anti-PD-1 treatment of mice harboring LDH-A deficient B16-F10 melanoma tumors led to an increase in anti-tumor immune responses compared to mice implanted with tumors expressing LDH-A. Specifically, we observed heightened infiltration of natural killer (NK) cells and CD8<sup>+</sup> cytotoxic T cells in the LDH-A deficient tumors. These infiltrated cytotoxic cells had an elevated production of interferon-γ (IFN-γ) and granzyme B. Mechanistically, CD8<sup>+</sup> T cells isolated from the TME of LDH-A deficient B16-F10 melanoma tumors and treated with anti-PD-1 showed enhanced mitochondrial activity and increased reactive oxygen species (ROS) levels. Moreover, infiltration of T regulatory (Treg) cells was diminished in LDH-A deficient tumors treated with anti-PD-1. These altered immune cell profiles were clinically relevant as they were accompanied by significantly reduced tumor growth. Our study suggests that blocking LDH-A in the tumor might improve the efficacy of anti-PD-1 therapy. |
| first_indexed | 2024-03-12T06:46:28Z |
| format | Article |
| id | doaj.art-b3d505641b654e959cd9a9ba9a4f7fb9 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:46:28Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-b3d505641b654e959cd9a9ba9a4f7fb92023-09-03T00:34:56ZengMDPI AGCancers2072-66942019-03-0111445010.3390/cancers11040450cancers11040450Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in MelanomaSaeed Daneshmandi0Barbara Wegiel1Pankaj Seth2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADepartment of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USAImmunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients. We have recently reported that programmed cell death protein-1 (PD-1) ligand (PD-L1) expression is regulated by lactate present at high levels in the tumor microenvironment (TME). We hypothesized that the efficacy of anti-PD-1 treatment can be improved by blocking the lactate-generating enzyme, lactate dehydrogenase-A (LDH-A). Anti-PD-1 treatment of mice harboring LDH-A deficient B16-F10 melanoma tumors led to an increase in anti-tumor immune responses compared to mice implanted with tumors expressing LDH-A. Specifically, we observed heightened infiltration of natural killer (NK) cells and CD8<sup>+</sup> cytotoxic T cells in the LDH-A deficient tumors. These infiltrated cytotoxic cells had an elevated production of interferon-γ (IFN-γ) and granzyme B. Mechanistically, CD8<sup>+</sup> T cells isolated from the TME of LDH-A deficient B16-F10 melanoma tumors and treated with anti-PD-1 showed enhanced mitochondrial activity and increased reactive oxygen species (ROS) levels. Moreover, infiltration of T regulatory (Treg) cells was diminished in LDH-A deficient tumors treated with anti-PD-1. These altered immune cell profiles were clinically relevant as they were accompanied by significantly reduced tumor growth. Our study suggests that blocking LDH-A in the tumor might improve the efficacy of anti-PD-1 therapy.https://www.mdpi.com/2072-6694/11/4/450LDH-AlactatePD-1PD-L1melanoma |
| spellingShingle | Saeed Daneshmandi Barbara Wegiel Pankaj Seth Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma Cancers LDH-A lactate PD-1 PD-L1 melanoma |
| title | Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma |
| title_full | Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma |
| title_fullStr | Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma |
| title_full_unstemmed | Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma |
| title_short | Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma |
| title_sort | blockade of lactate dehydrogenase a ldh a improves efficacy of anti programmed cell death 1 pd 1 therapy in melanoma |
| topic | LDH-A lactate PD-1 PD-L1 melanoma |
| url | https://www.mdpi.com/2072-6694/11/4/450 |
| work_keys_str_mv | AT saeeddaneshmandi blockadeoflactatedehydrogenasealdhaimprovesefficacyofantiprogrammedcelldeath1pd1therapyinmelanoma AT barbarawegiel blockadeoflactatedehydrogenasealdhaimprovesefficacyofantiprogrammedcelldeath1pd1therapyinmelanoma AT pankajseth blockadeoflactatedehydrogenasealdhaimprovesefficacyofantiprogrammedcelldeath1pd1therapyinmelanoma |