31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Adoptive Cellular TherapyO1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cellsAndreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1, Rolf Kiessling1, Yumeng Mao11Karolinska Institutet, Stockholm, Stockholms Lan, Sweden; 2Weill Cornell Medical College, New York, NY, USA; 3Nova Southeastern University, Cell Therapy Institute, Fort Lauderdale, FL, USACorrespondence: Andreas Lundqvist (andreas.lundqvist@ki.se) Background NK cell-based immunotherapy is a potential therapeutic modality in patients with advanced cancers as transfer of haploidentical NK cells induces beneficial responses in patients with hematological malignancies; and leukemia clearance correlates with persistence and in vivo expansion of NK cells after infusion. Thus, sustained NK cell activity in vivo likely represents a therapy performance-limiting factor. Methods We performed genome-wide analysis of cytosolic and polysome-associated mRNA from interleukin (IL)-2 and IL-15 activated NK cells. Furthermore, the ability of IL-2 and IL-15 to sustain human NK cell activity following cytokine withdrawal as well as their effect on NK cells to resist tumor-induced immunosuppression was compared. Results After cytokine withdrawal, IL-15-treated NK cells maintained a higher level of cytotoxicity (p < 0.05) and showed lower levels of apoptosis (p < 0.05) compared with cells treated with IL-2. IL-15 augmented mTOR signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced cell function advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK cell function during cytokine activation but not following cytokine withdrawal. Upon co-culture with tumor cells or exposure to tumor cell supernatant, IL-15 activated NK cell maintained a significantly higher level of proliferation and cytotoxic activity (p < 0.05). Mechanistically, tumor-derived prostaglandin-E2 suppressed IL-2 cultured NK cells while IL-15 cultured NK cells remained activated. The superior performance of IL-15 stimulated NK cells was also observed using a clinically applicable protocol for NK cell expansion in vitro and in vivo. Conclusions This study adds to our understanding about establishment and maintenance of tumor-reactive NK cells and suppo