NK Receptors Replace CD28 As the Dominant Source of Signal 2 for Cognate Recognition of Cancer Cells by TAA-specific Effector CD8+ T Cells

Abstract

CD28-driven “signal 2” is critical for naïve CD8+ 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.

MHC1/LILRB1 axis as an innate immune checkpoint for cancer therapy

“…This interaction contributes to the stability of the peptide-MHC complex and determines the recognition by cytotoxic T lymphocytes (CTLs), leading to the mobilization of adaptive immunity (8). In the context of cancer immunology, orchestrating immune recognition of MHC1 molecules is responsible for presenting fragments of tumor-specific proteins (antigens) to CTLs which serves as the fundamental step for immune system to identify and eliminate cancer cells (9,10).…”