A possible new pathway in natural killer cell activation also reveals the difficulty in determining human NK cell function in cancer.

Immunotherapy is rapidly becoming the fourth arm of cancer treatment, and breakthrough successes have been observed in multiple malignancies. However, despite the potential for impressive anti-tumor effects, on average, only 25% of patients respond, and barriers clearly remain. Hence, uncovering innovative ways to apply immunotherapy and overcome immune resistance remains an unmet need in immuno-oncology. Natural killer (NK) cells are an attractive candidate for extending the promise of immunotherapy, although success to date has been largely limited to hematological cancers. An important study has identified novel ways in which NK cells sense and respond to tumors, and these findings may impact clinical translation of NK cells in cancer immunotherapy. Using the activating receptor NKp44, NK cells were shown to bind platelet-derived growth factor DD (PDGF-DD) which was secreted by tumors. Using transgenic mice, NKp44 binding of tumor-expressed PDGF-DD was able to limit tumor growth, and expression of natural cytotoxicity receptor-associated gene signatures (of which NKp44 is a member) was correlated to clinical outcomes. This study highlights the potential for effector-target interactions to impact immune homeostasis in previously unrecognized ways, while at the same time, underscoring the complexities inherent in pre-clinical/ translational experimental design which may confound clinical application of these interesting results.