CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D–NKG2DL axis

Abstract

The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D–NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants.

Layer-by-layer nanoparticle encapsulating all-trans retinoic acid and CpG as a mucosal adjuvant targeting colorectal cancer

“…These CD8 + T cells recognize OVA antigen. 35,36 We treated these CD8 + T cells using ATRA@CpG-NPs with or without OVA and detected the content of IL-2 and IFN-γ in the supernatants. Cells treated with ATRA@CpG-NPs + OVA secrete significantly higher amounts of IL-2 and IFN-γ compared to those treated with ATRA@CpG-NPs and PBS treatment, suggesting that ATRA@CpG-NPs + OVA could activate antigen-specific CD8 + T cells (Fig.…”

Comprehensive analysis of KLF family reveals KLF6 as a promising prognostic and immune biomarker in pancreatic ductal adenocarcinoma

“…Enrichment analysis demonstrated that patients in cluster 1 exhibited increased activation of cancer-related pathways, including hypoxia, glycolysis, and the p53 pathway. TIME is infiltrated by a variety of immune cells, among which CD8 + or cytotoxic T lymphocytes exert tumor-killing function, while regulatory T cells attenuate effector T cell activity and promote immunosuppression in TIME [ 28 , 29 ]. Different immune cell ratios could promote tumor growth and metastasis by shaping TIME and thus mediating the immune escape of tumor cells [ 30 ].…”

Cancer-associated fibroblasts serve as decoys to suppress NK cell anti-cancer cytotoxicity

“…In a previous study we also observed a sharp increase in stromal expression of Nectin2 in BRCA2 mutated pancreatic cancer patients, with inhibitory effects on cytotoxic CD8+ T-cells 16 , raising the possibility of its use as a stromal biomarker in different cancers. Thus, the spatial organization and quantity of CAFs in tumors may dictate reduction of cytotoxic lymphocyte activity via the NKG2D-DNAM-1 axis, since both NK cells and CD8+ T-cells rely on these receptors for immune-surveillance 92,93 . On the other hand, the observation that CAFs upregulate NKG2D and DNAM-1 ligands also opens the possibility of utilizing activated NK cells to modulate solid tumors that are characterized by high desmoplasia as a combinatorial immunotherapeutic approach; One interesting avenue may incorporate adoptive NK cell administration followed by conventional checkpoint blockade that may initially reduce stromal content, and therefore provide potent synergistic effects in solid tumors.…”