The PD-L1 metabolic interactome intersects with choline metabolism and inflammation
Abstract Background Harnessing the power of the immune system by using immune checkpoint inhibitors has resulted in some of the most exciting advances in cancer treatment. The full potential of this approach has, however, not been fully realized for treating many cancers such as pancreatic and breas...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-02-01
|
| Series: | Cancer & Metabolism |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40170-021-00245-w |
| _version_ | 1818965786732003328 |
|---|---|
| author | Jesus Pacheco-Torres Marie-France Penet Yelena Mironchik Balaji Krishnamachary Zaver M. Bhujwalla |
| author_facet | Jesus Pacheco-Torres Marie-France Penet Yelena Mironchik Balaji Krishnamachary Zaver M. Bhujwalla |
| author_sort | Jesus Pacheco-Torres |
| collection | DOAJ |
| description | Abstract Background Harnessing the power of the immune system by using immune checkpoint inhibitors has resulted in some of the most exciting advances in cancer treatment. The full potential of this approach has, however, not been fully realized for treating many cancers such as pancreatic and breast cancer. Cancer metabolism influences many aspects of cancer progression including immune surveillance. An expanded understanding of how cancer metabolism can directly impact immune checkpoints may allow further optimization of immunotherapy. We therefore investigated, for the first time, the relationship between the overexpression of choline kinase-α (Chk-α), an enzyme observed in most cancers, and the expression of the immune checkpoint PD-L1. Methods We used small interfering RNA to downregulate Chk-α, PD-L1, or both in two triple-negative human breast cancer cell lines (MDA-MB-231 and SUM-149) and two human pancreatic ductal adenocarcinoma cell lines (Pa09C and Pa20C). The effects of the downregulation were studied at the genomic, proteomic, and metabolomic levels. The findings were compared with the results obtained by the analysis of public data from The Cancer Genome Atlas Program. Results We identified an inverse dependence between Chk-α and PD-L1 at the genomic, proteomic, and metabolomic levels. We also found that prostaglandin-endoperoxide synthase 2 (COX-2) and transforming growth factor beta (TGF-β) play an important role in this relationship. We independently confirmed this relationship in human cancers by analyzing data from The Cancer Genome Atlas Program. Conclusions Our data identified previously unknown roles of PD-L1 in cancer cell metabolic reprogramming, and revealed the immunosuppressive increased PD-L1 effect of Chk-α downregulation. These data suggest that PD-L1 regulation of metabolism may be mediated through Chk-α, COX-2, and TGF-β. The observations provide new insights that can be applied to the rational design of combinatorial therapies targeting immune checkpoints and cancer metabolism. |
| first_indexed | 2024-12-20T13:22:33Z |
| format | Article |
| id | doaj.art-8db68ae8c2c048e9baa726a3d17de458 |
| institution | Directory Open Access Journal |
| issn | 2049-3002 |
| language | English |
| last_indexed | 2024-12-20T13:22:33Z |
| publishDate | 2021-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer & Metabolism |
| spelling | doaj.art-8db68ae8c2c048e9baa726a3d17de4582022-12-21T19:39:22ZengBMCCancer & Metabolism2049-30022021-02-019111610.1186/s40170-021-00245-wThe PD-L1 metabolic interactome intersects with choline metabolism and inflammationJesus Pacheco-Torres0Marie-France Penet1Yelena Mironchik2Balaji Krishnamachary3Zaver M. Bhujwalla4Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of MedicineDivision of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of MedicineDivision of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of MedicineDivision of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of MedicineDivision of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of MedicineAbstract Background Harnessing the power of the immune system by using immune checkpoint inhibitors has resulted in some of the most exciting advances in cancer treatment. The full potential of this approach has, however, not been fully realized for treating many cancers such as pancreatic and breast cancer. Cancer metabolism influences many aspects of cancer progression including immune surveillance. An expanded understanding of how cancer metabolism can directly impact immune checkpoints may allow further optimization of immunotherapy. We therefore investigated, for the first time, the relationship between the overexpression of choline kinase-α (Chk-α), an enzyme observed in most cancers, and the expression of the immune checkpoint PD-L1. Methods We used small interfering RNA to downregulate Chk-α, PD-L1, or both in two triple-negative human breast cancer cell lines (MDA-MB-231 and SUM-149) and two human pancreatic ductal adenocarcinoma cell lines (Pa09C and Pa20C). The effects of the downregulation were studied at the genomic, proteomic, and metabolomic levels. The findings were compared with the results obtained by the analysis of public data from The Cancer Genome Atlas Program. Results We identified an inverse dependence between Chk-α and PD-L1 at the genomic, proteomic, and metabolomic levels. We also found that prostaglandin-endoperoxide synthase 2 (COX-2) and transforming growth factor beta (TGF-β) play an important role in this relationship. We independently confirmed this relationship in human cancers by analyzing data from The Cancer Genome Atlas Program. Conclusions Our data identified previously unknown roles of PD-L1 in cancer cell metabolic reprogramming, and revealed the immunosuppressive increased PD-L1 effect of Chk-α downregulation. These data suggest that PD-L1 regulation of metabolism may be mediated through Chk-α, COX-2, and TGF-β. The observations provide new insights that can be applied to the rational design of combinatorial therapies targeting immune checkpoints and cancer metabolism.https://doi.org/10.1186/s40170-021-00245-wImmune checkpointsPD-L1Choline kinase alphaCOX-2Breast cancer |
| spellingShingle | Jesus Pacheco-Torres Marie-France Penet Yelena Mironchik Balaji Krishnamachary Zaver M. Bhujwalla The PD-L1 metabolic interactome intersects with choline metabolism and inflammation Cancer & Metabolism Immune checkpoints PD-L1 Choline kinase alpha COX-2 Breast cancer |
| title | The PD-L1 metabolic interactome intersects with choline metabolism and inflammation |
| title_full | The PD-L1 metabolic interactome intersects with choline metabolism and inflammation |
| title_fullStr | The PD-L1 metabolic interactome intersects with choline metabolism and inflammation |
| title_full_unstemmed | The PD-L1 metabolic interactome intersects with choline metabolism and inflammation |
| title_short | The PD-L1 metabolic interactome intersects with choline metabolism and inflammation |
| title_sort | pd l1 metabolic interactome intersects with choline metabolism and inflammation |
| topic | Immune checkpoints PD-L1 Choline kinase alpha COX-2 Breast cancer |
| url | https://doi.org/10.1186/s40170-021-00245-w |
| work_keys_str_mv | AT jesuspachecotorres thepdl1metabolicinteractomeintersectswithcholinemetabolismandinflammation AT mariefrancepenet thepdl1metabolicinteractomeintersectswithcholinemetabolismandinflammation AT yelenamironchik thepdl1metabolicinteractomeintersectswithcholinemetabolismandinflammation AT balajikrishnamachary thepdl1metabolicinteractomeintersectswithcholinemetabolismandinflammation AT zavermbhujwalla thepdl1metabolicinteractomeintersectswithcholinemetabolismandinflammation AT jesuspachecotorres pdl1metabolicinteractomeintersectswithcholinemetabolismandinflammation AT mariefrancepenet pdl1metabolicinteractomeintersectswithcholinemetabolismandinflammation AT yelenamironchik pdl1metabolicinteractomeintersectswithcholinemetabolismandinflammation AT balajikrishnamachary pdl1metabolicinteractomeintersectswithcholinemetabolismandinflammation AT zavermbhujwalla pdl1metabolicinteractomeintersectswithcholinemetabolismandinflammation |