Various approaches to activate NK cells are being increasingly explored in clinical trials against cancer. presentation machinery. Thus, NK cells may serve as useful effectors against tumor cells that have become resistant to classical immune checkpoint therapy. Various approaches to activate NK cells are being increasingly explored in clinical trials against cancer. While clinical benefit has been demonstrated in patients with acute myeloid leukemia receiving haploidentical NK cells, responses in patients with solid tumors are so far less encouraging. Several hurdles need to be overcome to provide meaningful clinical responses in patients with solid tumors. Here we review the recent developments to augment NK cell responses against solid tumors with regards to cytokine therapy, mAChR-IN-1 hydrochloride adoptive infusion of NK cells, NK cell engagers, and NK cell immune checkpoints. growth of T Rabbit Polyclonal to p53 cell and Natural killer (NK) cell subsets [1,2,3,4]. NK cells were discovered in the mid 70s based on their natural capacity to kill tumor cells without prior sensitization [5,6]. In contrast to T cells, NK cells sense the absence of self Major Histocompatibility Complex (MHC) class I molecules through stochastically expressed inhibitory receptors. This suggests that NK cells may be particularly effective when transferred across HLA barriers [7,8]. In addition to antibody-independent cytotoxicity, the expression of CD16 on a majority of NK cells renders them strong mediators of antibody dependent cellular cytotoxicity (ADCC). Taking advantage of this, various mAbs have been developed and have now become the standard of care in various hematological and solid cancers, including rituximab, cetuximab and trastuzumab. Other routes by which NK cells can kill targets are the death receptor pathways Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/TRAIL-R and Fas/FasL. Instead of triggering the release of cytotoxic granules, death receptor pathways prompt apoptosis via caspase activation in target cells. Although NK cell therapy has been successful in targeting hematological malignancies, the outcome of adoptive NK cell infusion into patients with solid tumors has been rather disappointing. One of the major challenges with NK cell-based therapies against solid tumors includes trafficking of NK cells to the tumor location and infiltration into the tumor. Several studies have shown that mAChR-IN-1 hydrochloride there is a correlation between the presence of NK cells at the tumor site and tumor progression [9,10,11]. Furthermore, the presence of inhibitory signals within the tumor microenvironment and altered immunogenicity of tumor cells also contributes to the poor infiltration and activation of NK cells mAChR-IN-1 hydrochloride at mAChR-IN-1 hydrochloride the tumor site . Increasing interest in NK cells over the past years has resulted in several ongoing clinical trials beginning to systematically address the potential role of NK cells in clinical settings. Intense research effort is now made to enhance NK cell function to target tumors. In this review we will discuss the recent developments in augmenting NK cell responses against solid tumors. 2. Cytokines Growth factors that belong to the common -chain cytokines including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21, play key functions in the development and homeostasis of T and NK cells . IL-2 activates NK cells via binding to the heterotrimeric IL-2 receptor that consists of the IL-2 receptor subunit alpha (CD25) and beta (CD122), and the common gamma chain (CD132). Patients undergoing treatment with adoptive NK cell therapy are often given IL-2 to sustain the growth of infused NK cells [13,14,15] (Table 1 1,2,3). However, recombinant IL-2 has a limited half-life and is associated with dose-limiting adverse events such as arrhythmias, heart failure and capillary leak syndrome that lead to life-threatening toxicities in patients. While the administration of low-dose IL-2 show a lower toxicity profile, little clinical benefit of IL-2 therapy was detected in matched-pairs analysis . Weekly administration of IL-2 together with interferon- can lead to exhaustion of NK cells, which may explain the low efficacy of IL-2 as a monotherapy . Table 1 Clinical trials (clinicaltrials.gov). 1 “type”:”clinical-trial”,”attrs”:”text”:”NCT00274846″,”term_id”:”NCT00274846″NCT00274846; Donor Peripheral Stem Cell Transplant in Treating Patients.