A Novel MHC-Independent Mechanism of Tumor Cell Killing by CD8⁺T Cells

Abstract

The accepted paradigm for both cellular and antitumor immunity relies upon tumor cell kill by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex 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 on interactions between T cell NKG2D and tumor NKG2D ligands (NKG2DL). Necessarily, tumor cell kill 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 tumors cells. 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. Tumor cell killing following T cell NKG2D engagement is Fas-independent and appears to involve granzyme. These studies potentially obviate 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 novel therapeutic target for enhancing T cell-dependent anti tumor immunity against MHC loss variants.

Dendritic cell targeting in lymph nodes with engineered modular adapters improves HAdV5 and HC-HAdV5 tumor vaccination by co-secretion of IL-2v and IL-21

“…The growth reduction of the B16-OVA MO4 metastasis model is described to be mainly dependent on cytotoxic CD8 + T cells, however, it is also under strong control of NK cells. 78,79 IHC staining of CD8 and CD161 revealed that NK and CD8 + T cells were seen in variable numbers within metastatic foci in all treatment groups. However, for progressed large metastatic foci, both cell types failed to reach the center (IHC data of CD8 and CD161 not shown).…”