NK Receptors Replace CD28 As the Dominant Source of Signal 2 for Cognate Recognition of Cancer Cells by TAA-specific Effector CD8+ T Cells
Year: 2023
Type: preprint
Abstract: T cell responses to dendritic cell (DC)-presented weak antigens, including non-mutated tumor-associated antigens (TAAs). However, it is unclear how DC-primed cytotoxic T lymphocytes (CTLs) respond to the same TAAs presented by cancer cells which lack CD28 ligands. Here, we show that NK receptors (NKRs) DNAM-1 and NKG2D replace CD28 during CTL re-activation by cancer cells presenting low levels of MHC I/TAA complexes, leading to enhanced proximal TCR signaling, immune synapse formation, CTL polyfunctionality, release of cytolytic granules and antigen-specific cancer cell killing. Double-transduction of T cells with recombinant TCR and NKR constructs or upregulation of NKR-ligand expression on cancer cells by chemotherapy enabled effective recognition and killing of poorly immunogenic tumor cells by CTLs. Operational synergy between TCR and NKRs in CTL recognition explains the ability of cancer-expressed self-antigens to serve as tumor rejection antigens, helping to develop more effective therapies.
Source: Research Square
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G2348382760, Targeting the Chemokine System to Sensitize Tumors to Immunotherapy, G3938307694, G4119534169, NOVEL IMMUNOTHERAPY FOR BRAIN-METASTATIC BREAST CANCER, G5850682332, Understanding mechanisms and consequences of T cell co-receptor regulated RNA maturation, Associate-Director Flow and Image Cytometry Roswell Park ComprehensiveCancer Center, Roswell Park Ovarian Cancer SPORE
OpenAlex ID: W4387732918