Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing Immunotherapy
While immune checkpoint (IC) therapies, particularly those targeting the PD-1/PD-L1 axis, have revolutionized the treatment of melanoma and several other cancers, their effect remains very limited in colorectal cancer (CRC). To define a comprehensive landscape of ICs in the human CRC tumor microenvi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/17/4261 |
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| author | Kathleen Ducoin Linda Bilonda-Mutala Cécile Deleine Romain Oger Emilie Duchalais Nicolas Jouand Céline Bossard Anne Jarry Nadine Gervois-Segain |
| author_facet | Kathleen Ducoin Linda Bilonda-Mutala Cécile Deleine Romain Oger Emilie Duchalais Nicolas Jouand Céline Bossard Anne Jarry Nadine Gervois-Segain |
| author_sort | Kathleen Ducoin |
| collection | DOAJ |
| description | While immune checkpoint (IC) therapies, particularly those targeting the PD-1/PD-L1 axis, have revolutionized the treatment of melanoma and several other cancers, their effect remains very limited in colorectal cancer (CRC). To define a comprehensive landscape of ICs in the human CRC tumor microenvironment (TME), we evaluated, using multiparametric flow cytometry, their ex vivo expression via tumor-infiltrating lymphocytes (TILs) (n = 40 CRCs) as well as that of their respective ligands on tumor and myeloid cells (n = 29). Supervised flow cytometry analyses showed that (i) most CD3<sup>+</sup> TILs expressed PD-1 and TIGIT and, to a lesser extent, Tim-3, Lag3 and NKG2A, and (ii) EpCAM<sup>+</sup> tumor cells and CD11b<sup>+</sup> myeloid cells differed in their IC ligand expression profile, with a strikingly high expression of CD155 by tumor cells. An in situ analysis of IC and their ligands using immunohistochemistry on paraffin sections of CRC confirmed the overexpression of TIGIT and its ligand, CD155, in the TME. Most interestingly, an unsupervised clustering analysis of IC co-expression on CD4<sup>+</sup> and CD8<sup>+</sup> TILs identified two tumor subgroups, named IC<sup>high</sup> and IC<sup>low</sup>. Altogether, our findings highlight the TIGIT/CD155 axis as a potential target that could be used in combination IC therapy in CRC. |
| first_indexed | 2024-03-10T01:57:51Z |
| format | Article |
| id | doaj.art-7249e516e9d541d4b74f1762d51f8c87 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:57:51Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-7249e516e9d541d4b74f1762d51f8c872023-11-23T12:52:35ZengMDPI AGCancers2072-66942022-08-011417426110.3390/cancers14174261Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing ImmunotherapyKathleen Ducoin0Linda Bilonda-Mutala1Cécile Deleine2Romain Oger3Emilie Duchalais4Nicolas Jouand5Céline Bossard6Anne Jarry7Nadine Gervois-Segain8Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, F-44000 Nantes, FranceLabEx IGO, Université de Nantes, F-44000 Nantes, FranceNantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, F-44000 Nantes, FranceLabEx IGO, Université de Nantes, F-44000 Nantes, FranceCHU Nantes, Department of Digestive Surgery and IMAD, F-44000 Nantes, FranceCytocell, BioCore, Nantes Université UMS 3556, Inserm US016, CNRS UAR 3556, CHU Nantes, SFR Santé François BONAMY, F-44000 Nantes, FranceCHU Nantes, Pathology Department, F-44000 Nantes, FranceNantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, F-44000 Nantes, FranceNantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, F-44000 Nantes, FranceWhile immune checkpoint (IC) therapies, particularly those targeting the PD-1/PD-L1 axis, have revolutionized the treatment of melanoma and several other cancers, their effect remains very limited in colorectal cancer (CRC). To define a comprehensive landscape of ICs in the human CRC tumor microenvironment (TME), we evaluated, using multiparametric flow cytometry, their ex vivo expression via tumor-infiltrating lymphocytes (TILs) (n = 40 CRCs) as well as that of their respective ligands on tumor and myeloid cells (n = 29). Supervised flow cytometry analyses showed that (i) most CD3<sup>+</sup> TILs expressed PD-1 and TIGIT and, to a lesser extent, Tim-3, Lag3 and NKG2A, and (ii) EpCAM<sup>+</sup> tumor cells and CD11b<sup>+</sup> myeloid cells differed in their IC ligand expression profile, with a strikingly high expression of CD155 by tumor cells. An in situ analysis of IC and their ligands using immunohistochemistry on paraffin sections of CRC confirmed the overexpression of TIGIT and its ligand, CD155, in the TME. Most interestingly, an unsupervised clustering analysis of IC co-expression on CD4<sup>+</sup> and CD8<sup>+</sup> TILs identified two tumor subgroups, named IC<sup>high</sup> and IC<sup>low</sup>. Altogether, our findings highlight the TIGIT/CD155 axis as a potential target that could be used in combination IC therapy in CRC.https://www.mdpi.com/2072-6694/14/17/4261immune checkpointsTIGITtumor-infiltrating lymphocytecolorectal cancerimmunotherapy |
| spellingShingle | Kathleen Ducoin Linda Bilonda-Mutala Cécile Deleine Romain Oger Emilie Duchalais Nicolas Jouand Céline Bossard Anne Jarry Nadine Gervois-Segain Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing Immunotherapy Cancers immune checkpoints TIGIT tumor-infiltrating lymphocyte colorectal cancer immunotherapy |
| title | Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing Immunotherapy |
| title_full | Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing Immunotherapy |
| title_fullStr | Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing Immunotherapy |
| title_full_unstemmed | Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing Immunotherapy |
| title_short | Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing Immunotherapy |
| title_sort | defining the immune checkpoint landscape in human colorectal cancer highlights the relevance of the tigit cd155 axis for optimizing immunotherapy |
| topic | immune checkpoints TIGIT tumor-infiltrating lymphocyte colorectal cancer immunotherapy |
| url | https://www.mdpi.com/2072-6694/14/17/4261 |
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