Our laboratory has since long been engaged in experimental studies of a human stimulatory lymphocyte receptor called NKG2D and its various ligands, and the mechanisms whereby these proteins contribute to immune responses against cancer and in autoimmune disease. The main emphasis has been on the capacity of NKG2D to promote tumor immune surveillance by cytotoxic natural killer (NK) cells and CD8 T cells upon engagement of ligands that are induced on cancer cells as a consequence of malignant tranformation. Observations made during those earlier studies revealed that progressing tumors stifle host immune responses by employing tactics to disable lymphocyte NKG2D functionality. Moreover, in a conceptual twist, this negative dynamic is escalated as some cancer cells (such as breast, colon, ovarian, and colon cancer cells) co-opt expression of NKG2D for their own benefit, complementing the presence of its ligands for autonomous stimulation of oncogenic signaling and tumor growth. Further advancing this model, clinical association data have implied a relationship between the presence of NKG2D on cancer cells and metastatic disease, suggesting that NKG2D signaling may promote cancer cell plasticity, thereby enabling cancer cells to dissociate from primary tumor, disseminate, and multiply at distant sites. Cancer cell NKG2D may thus have the capacity to drive high malignancy traits underlying metastatic disease. Recently completed and ongoing studies are in the following areas:
Cancer cell plasticity is regulated by the epithelial–mesenchymal transition and the interrelated acquisition of regenerative cancer stem cell traits. We have shown that NKG2D signaling promotes phenotypic, molecular, and functional signatures diagnostic of the epithelial–mesenchymal transition, and of stem-like traits via induction of Sox9, a key transcriptional regulator of breast stem cell maintenance. These findings obtained with model breast tumor lines and xenotransplants in immunodeficient mice were recapitulated by human ex vivo cancer cells from primary invasive breast carcinomas. Evaluation of mice transplanted with human tumor lines confirmed profound NKG2D effects on tumor initiation, growth and distant metastasis. Current studies address the role of cancer cell NKG2D in cancer stem cell reprogramming in vivo and its pathophysiological significance in clinical settings.