Modeling natural killer cell responses against lung cancer (TUM2P.917)

Abstract

Abstract Natural killer (NK) cells are innate lymphocytes that recognize and kill transformed and pathogen-infected cells. Thought to act as a first line of defense in immune surveillance, NK cells secrete inflammatory cytokines that stimulate adaptive immune responses. Thus, the quality of NK cell responses may impact the potency of adaptive responses against cancer and, perhaps, the efficacy of immunotherapy in individual patients. In a Kras and p53-driven model of autochthonous non-small cell lung cancer, we observe dysfunctional phenotypes in infiltrating NK cells, similar to what is seen in human disease. We have adapted this model to study NK cell responses against lung cancer in a targeted manner, by inducing expression of potent model NK cell ligands in developing tumors. Induced expression of the MCMV surface protein, m157, triggers robust lymphocytic infiltration in tumors within 6 days of induction. Infiltrates include NK cells as well as large numbers of T cells and B cells. Recruitment of T cells and B cells upon ligand induction is dependent on NK cells, and on the interaction of m157 with the Ly49H activating receptor expressed on NK cells. This work demonstrates that NK cells residing in or near established tumors can be stimulated by activating ligands, and that this stimulation leads to the recruitment of adaptive immune responses at the site of tumors. Future work will dissect the mechanisms by which activated NK cells recruit T cells and B cells to tumors.