X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich Syndrome protein (WASp). XLN patients have reduced numbers of cytotoxic cells in peripheral blood, however, their capacity to kill tumor cells remains to be determined. Here, we examined NK and T cells from two XLN patients harboring the activating WASpL270P mutation. XLN patient NK and T cells had increased Granzyme B content and elevated degranulation and IFNγ production when compared to healthy control cells. Murine WASpL272P NK and T cells formed stable synapses with YAC-1 tumor cells and anti-CD3/CD28 coated beads, respectively. WASpL272P T cells mice had normal degranulation and cytokine response whereas WASpL272P NK cells showed an enhanced response. Imaging experiments revealed that while WASpL272P CD8 T cells had increased accumulation of actin upon TCR activation, WASpL272P NK cells had normal actin accumulation at lytic synapses triggered through NKp46 signaling but had impaired response to LFA-1 engagement. When compared to WT mice, WASpL272P mice showed reduced growth of B16 melanoma and increased capacity to reject MHC class I-deficient cells. Together, our data suggests that cytotoxic cells with constitutively active WASp have an increased capacity to respond to and kill tumor cells.
Joanna S. Kritikou, Mariana M.S. Oliveira, Julien Record, Mezida B. Saeed, Saket M. Nigam, Minghui He, Marton Keszei, Arnika K. Wagner, Hanna Brauner, Anton Sendel, Saikiran K. Sedimbi, Stamatina Rentouli, David P. Lane, Scott B. Snapper, Klas Kärre, Peter Vandenberghe, Jordan S. Orange, Lisa S. Westerberg