LAG3 and TIGIT Expression on Tumor Infiltrating Lymphocytes in Cutaneous Melanoma.
Journal
Dermatology (Basel, Switzerland)
ISSN: 1421-9832
Titre abrégé: Dermatology
Pays: Switzerland
ID NLM: 9203244
Informations de publication
Date de publication:
11 Nov 2023
11 Nov 2023
Historique:
received:
13
03
2023
accepted:
31
08
2023
medline:
13
11
2023
pubmed:
13
11
2023
entrez:
12
11
2023
Statut:
aheadofprint
Résumé
Melanoma is widely recognized to be an immunogenic tumor that often contains tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME).During cancer progression, expression of ligands that bind immune checkpoint (IC) proteins, such as PD1, expressed on the surface of TILs, hinder them from exerting their antitumor functions. TILs consist of a heterogenous group of immune cells and their presence is associated with an improved overall survival (OS) in melanoma patients. Introduction of IC inhibitors has revolutionized management and prognosis of advanced melanoma. Unfortunately, the response rates have continued to be limited, resulting in growing interest in characterizing novel IC proteins, and developing combination therapy that includes inhibitors against multiple IC proteins. In a regional cohort of 166 patients diagnosed with cutaneous superficial spreading melanoma (SSM) with different degree of TILs, we investigated the tumor-immune associated gene expression profile using NanoString Technology. We used multiplex immunofluorescence (mIF) staining in a subset of tumors (N=7), combining IC proteins TIGIT and LAG3 with a melanoma cell marker (SOX10) and immune cell markers (CD8 (cytotoxic T cells), CD4 (T helper cells), FOXP3 (regulatory T cells/Tregs), PAX5 (B cells), and CD56 (NK/NKT cells)) and IC protein PD1. We found upregulation of 91 differentially expressed genes, including IC proteins, LAG3 and TIGIT in melanomas with brisk TILs compared to tumors where TILs were absent. mIF staining revealed LAG3 and TIGIT expression in the majority of CD8+ T cells. Only few Tregs and CD4+ T cells expressed LAG3, whereas majority of them expressed TIGIT. LAG3 and TIGIT were expressed in a small fraction of the NK/NKT cells and lacked in the B cells. The majority of PD1+ cells co-localized with LAG3 and TIGIT. We report a variable expression of LAG3 and TIGIT on TILs subtypes and a coeval occurrence with PD1. This knowledge places LAG3 and TIGIT in spatial and cellular context in melanoma. The data suggest that targeting multiple IC proteins might help to overcome the current challenges with IC therapies.
Sections du résumé
BACKGROUND
BACKGROUND
Melanoma is widely recognized to be an immunogenic tumor that often contains tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME).During cancer progression, expression of ligands that bind immune checkpoint (IC) proteins, such as PD1, expressed on the surface of TILs, hinder them from exerting their antitumor functions. TILs consist of a heterogenous group of immune cells and their presence is associated with an improved overall survival (OS) in melanoma patients. Introduction of IC inhibitors has revolutionized management and prognosis of advanced melanoma. Unfortunately, the response rates have continued to be limited, resulting in growing interest in characterizing novel IC proteins, and developing combination therapy that includes inhibitors against multiple IC proteins.
METHODS
METHODS
In a regional cohort of 166 patients diagnosed with cutaneous superficial spreading melanoma (SSM) with different degree of TILs, we investigated the tumor-immune associated gene expression profile using NanoString Technology. We used multiplex immunofluorescence (mIF) staining in a subset of tumors (N=7), combining IC proteins TIGIT and LAG3 with a melanoma cell marker (SOX10) and immune cell markers (CD8 (cytotoxic T cells), CD4 (T helper cells), FOXP3 (regulatory T cells/Tregs), PAX5 (B cells), and CD56 (NK/NKT cells)) and IC protein PD1.
RESULTS
RESULTS
We found upregulation of 91 differentially expressed genes, including IC proteins, LAG3 and TIGIT in melanomas with brisk TILs compared to tumors where TILs were absent. mIF staining revealed LAG3 and TIGIT expression in the majority of CD8+ T cells. Only few Tregs and CD4+ T cells expressed LAG3, whereas majority of them expressed TIGIT. LAG3 and TIGIT were expressed in a small fraction of the NK/NKT cells and lacked in the B cells. The majority of PD1+ cells co-localized with LAG3 and TIGIT.
CONCLUSION
CONCLUSIONS
We report a variable expression of LAG3 and TIGIT on TILs subtypes and a coeval occurrence with PD1. This knowledge places LAG3 and TIGIT in spatial and cellular context in melanoma. The data suggest that targeting multiple IC proteins might help to overcome the current challenges with IC therapies.
Identifiants
pubmed: 37952520
pii: 000533932
doi: 10.1159/000533932
doi:
Types de publication
News
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
The Author(s). Published by S. Karger AG, Basel.