The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas
Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (T<sub&g...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-09-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/18/4683 |
| _version_ | 1797519997709320192 |
|---|---|
| author | Marcos Garcia-Lacarte Sara C. Grijalba Javier Melchor Adrián Arnaiz-Leché Sergio Roa |
| author_facet | Marcos Garcia-Lacarte Sara C. Grijalba Javier Melchor Adrián Arnaiz-Leché Sergio Roa |
| author_sort | Marcos Garcia-Lacarte |
| collection | DOAJ |
| description | Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (T<sub>FH</sub>) and regulatory T (T<sub>FR</sub>) or B (Breg) cells are involved in positive selection of GC B cells and may result critical in the lymphoma microenvironment. Here, we discuss a role of PD-1/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of T<sub>FR</sub> cells and limiting IL-21-mediated anti-tumour functions of T<sub>FH</sub> cells and maximize the use of PD-1/PD-L1 signaling to escape from CD8<sup>+</sup> cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1/PD-L1-based combinational immunotherapies in DLBCL. |
| first_indexed | 2024-03-10T07:50:38Z |
| format | Article |
| id | doaj.art-b9f13c716bf641b78ad8ae398f30198d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T07:50:38Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-b9f13c716bf641b78ad8ae398f30198d2023-11-22T12:18:59ZengMDPI AGCancers2072-66942021-09-011318468310.3390/cancers13184683The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell LymphomasMarcos Garcia-Lacarte0Sara C. Grijalba1Javier Melchor2Adrián Arnaiz-Leché3Sergio Roa4Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, SpainDepartment of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, SpainDepartment of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, SpainDepartment of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, SpainDepartment of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, SpainBesides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (T<sub>FH</sub>) and regulatory T (T<sub>FR</sub>) or B (Breg) cells are involved in positive selection of GC B cells and may result critical in the lymphoma microenvironment. Here, we discuss a role of PD-1/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of T<sub>FR</sub> cells and limiting IL-21-mediated anti-tumour functions of T<sub>FH</sub> cells and maximize the use of PD-1/PD-L1 signaling to escape from CD8<sup>+</sup> cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1/PD-L1-based combinational immunotherapies in DLBCL.https://www.mdpi.com/2072-6694/13/18/4683immune checkpointgerminal centerlymphomaGC B cellsT follicular helper cellsT follicular regulatory cells |
| spellingShingle | Marcos Garcia-Lacarte Sara C. Grijalba Javier Melchor Adrián Arnaiz-Leché Sergio Roa The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas Cancers immune checkpoint germinal center lymphoma GC B cells T follicular helper cells T follicular regulatory cells |
| title | The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas |
| title_full | The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas |
| title_fullStr | The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas |
| title_full_unstemmed | The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas |
| title_short | The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas |
| title_sort | pd 1 pd l1 checkpoint in normal germinal centers and diffuse large b cell lymphomas |
| topic | immune checkpoint germinal center lymphoma GC B cells T follicular helper cells T follicular regulatory cells |
| url | https://www.mdpi.com/2072-6694/13/18/4683 |
| work_keys_str_mv | AT marcosgarcialacarte thepd1pdl1checkpointinnormalgerminalcentersanddiffuselargebcelllymphomas AT saracgrijalba thepd1pdl1checkpointinnormalgerminalcentersanddiffuselargebcelllymphomas AT javiermelchor thepd1pdl1checkpointinnormalgerminalcentersanddiffuselargebcelllymphomas AT adrianarnaizleche thepd1pdl1checkpointinnormalgerminalcentersanddiffuselargebcelllymphomas AT sergioroa thepd1pdl1checkpointinnormalgerminalcentersanddiffuselargebcelllymphomas AT marcosgarcialacarte pd1pdl1checkpointinnormalgerminalcentersanddiffuselargebcelllymphomas AT saracgrijalba pd1pdl1checkpointinnormalgerminalcentersanddiffuselargebcelllymphomas AT javiermelchor pd1pdl1checkpointinnormalgerminalcentersanddiffuselargebcelllymphomas AT adrianarnaizleche pd1pdl1checkpointinnormalgerminalcentersanddiffuselargebcelllymphomas AT sergioroa pd1pdl1checkpointinnormalgerminalcentersanddiffuselargebcelllymphomas |