NK Receptor Signaling Lowers TCR Activation Threshold, Enhancing Selective Recognition of Cancer Cells by TAA-Specific CTLs.
Details
Serval ID
serval:BIB_FD8D61C3442B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
NK Receptor Signaling Lowers TCR Activation Threshold, Enhancing Selective Recognition of Cancer Cells by TAA-Specific CTLs.
Journal
Cancer immunology research
ISSN
2326-6074 (Electronic)
ISSN-L
2326-6066
Publication state
Published
Issued date
01/10/2024
Peer-reviewed
Oui
Volume
12
Number
10
Pages
1421-1437
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
Cytotoxic CD8+ T lymphocyte (CTL) recognition of non-mutated tumor-associated antigens (TAA), present on cancer cells and also in healthy tissues, is an important element of cancer immunity, but the mechanism of its selectivity for cancer cells and opportunities for its enhancement remain elusive. In this study, we found that CTL expression of the NK receptors (NKR) DNAM1 and NKG2D was associated with the effector status of CD8+ tumor-infiltrating lymphocytes and long-term survival of patients with melanoma. Using MART1 and NY-ESO-1 as model TAAs, we demonstrated that DNAM1 and NKG2D regulate T-cell receptor (TCR) functional avidity and set the threshold for TCR activation of human TAA-specific CTLs. Superior co-stimulatory effects of DNAM1 over CD28 involved enhanced TCR signaling, CTL killer function, and polyfunctionality. Double transduction of human CTLs with TAA-specific TCR and NKRs resulted in strongly enhanced antigen sensitivity, without a reduction in antigen specificity and selectivity of killer function. In addition, the elevation of NKR ligand expression on cancer cells due to chemotherapy also increased CTL recognition of cancer cells expressing low levels of TAAs. Our data help explain the ability of self-antigens to mediate tumor rejection in the absence of autoimmunity and support the development of dual-targeting adoptive T-cell therapies that use NKRs to enhance the potency and selectivity of recognition of TAA-expressing cancer cells.
Keywords
Humans, Receptors, Antigen, T-Cell/metabolism, Receptors, Antigen, T-Cell/immunology, Signal Transduction, T-Lymphocytes, Cytotoxic/immunology, T-Lymphocytes, Cytotoxic/metabolism, Antigens, Neoplasm/immunology, Antigens, Neoplasm/metabolism, Melanoma/immunology, Melanoma/metabolism, NK Cell Lectin-Like Receptor Subfamily K/metabolism, Lymphocyte Activation/immunology, Lymphocytes, Tumor-Infiltrating/immunology, Lymphocytes, Tumor-Infiltrating/metabolism, Antigens, Differentiation, T-Lymphocyte/metabolism, Antigens, Differentiation, T-Lymphocyte/immunology, Cell Line, Tumor, MART-1 Antigen/immunology, MART-1 Antigen/metabolism, Cytotoxicity, Immunologic
Pubmed
Web of science
Create date
11/07/2024 14:22
Last modification date
31/10/2024 7:13