Lerner and Woroniecka et al. showed that CD8+ T cell-dependent immunotherapies remain effective against β2m-lacking tumor cells, independent of NK cells, via CD8+ T cell-mediated cytotoxicity, despite the absence of MHC-I in both murine and human tumor models. Antigen-independent T cell cytotoxicity is dependent on interactions between T cell NKG2D and its ligands (NKG2DLs) on MHC-I-loss tumor cells. Tumor cell killing relied on prior TCR activation, even with tumor-irrelevant antigen, and involved cytotoxic degranulation with granzyme and perforin, but did not depend on Fas-mediated cell death.
Contributed by Shishir Pant
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.
Author Info: (1) Duke University School of Medicine, Durham, NC, USA. Department of Biomedical Engineering, Duke University, Durham, NC, USA. (2) Department of Pathology, Duke University Medica
Author Info: (1) Duke University School of Medicine, Durham, NC, USA. Department of Biomedical Engineering, Duke University, Durham, NC, USA. (2) Department of Pathology, Duke University Medical Center, Durham, NC, USA. (3) Duke University School of Medicine, Durham, NC, USA. (4) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (5) Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (6) Department of Immunology, Duke University Medical Center, Durham, NC, USA. (7) Department of Pathology, Duke University Medical Center, Durham, NC, USA. (8) Duke University School of Medicine, Durham, NC, USA. Department of Pathology, Duke University Medical Center, Durham, NC, USA. (9) Department of Pathology, Duke University Medical Center, Durham, NC, USA. (10) Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (11) Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (12) Duke University School of Medicine, Durham, NC, USA. (13) Department of Immunology, Duke University Medical Center, Durham, NC, USA. (14) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (15) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (16) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA. (17) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. (18) Department of Immunology, Duke University Medical Center, Durham, NC, USA. Department of Medicine, Duke University Medical Center, Durham, NC, USA. (19) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. peter.fecci@duke.edu. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. peter.fecci@duke.edu.
