Till M. Theilen

We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis.

Abstract The induction of apoptosis is a direct way to eliminate tumor cells and improve cancer therapy. Apoptosis is tightly controlled by the balance of pro- and antiapoptotic Bcl-2 proteins. BH3 mimetics neutralize the antiapoptotic function of Bcl-2 proteins and are highly promising compounds inducing apoptosis in several cancer entities including pediatric malignancies. However, the clinical application of BH3 mimetics in solid tumors is impeded by the frequent resistance to single BH3 mimetics and the anticipated toxicity of high concentrations or combination treatments. One potential avenue to increase the potency of BH3 mimetics is the development of immune cell-based therapies to counteract the intrinsic apoptosis resistance of tumor cells and sensitize them to immune attack. Here, we describe spheroid cultures of pediatric cancer cells that can serve as models for drug testing. In these 3D models, we were able to demonstrate that activated allogeneic Natural Killer (NK) cells migrated into tumor spheroids and displayed cytotoxicity against a wide range of pediatric cancer spheroids, highlighting their potential as anti-tumor effector cells. Next, we investigated whether treatment of tumor spheroids with subtoxic concentrations of BH3 mimetics can increase the cytotoxicity of NK cells. Notably, the cytotoxic effects of NK cells were enhanced by the addition of BH3 mimetics. Treatment with either the Bcl-X L inhibitor A1331852 or the Mcl-1 inhibitor S63845 increased the cytotoxicity of NK cells and reduced spheroid size, while the Bcl-2 inhibitor ABT-199 had no effect on NK cell-mediated killing. Taken together, this is the first study to describe the combination of BH3 mimetics targeting Bcl-X L or Mcl-1 with NK cell-based immunotherapy, highlighting the potential of BH3 mimetics in immunotherapy.

Malignant esophageal tumors are exceedingly rare in children and adolescents. We present 3 cases of esophageal adenocarcinoma (AC) and squamous cell carcinoma (SSC) in patients ≤21 years of age who were treated at our institution between 1950 and 2015. We also undertook an analysis of those cases, combined with cases from a review of the literature, to examine patient demographics, disease characteristics, and outcomes. We identified one patient with AC and two patients with SCC treated at our institution, as well as 19 cases of AC (median age 16) and 23 cases of SCC (median age 15) reported in the literature. Male predominance was noted at a ratio of 2.2 to 1. Dysphagia, weight loss, and anemia were the most common presenting symptoms for both entities. Approximately 84% of AC tumors were located in the distal esophagus and gastroesophageal junction whereas SCC tumors were distributed evenly throughout esophagus. Metastatic disease at presentation was found in 68.4% of patients with AC compared to 30.4% of those with SCC. Survival was not significantly different between SCC and AC (P = 0.36), between genders (P = 0.13), and between patients treated with surgery vs. multimodality therapy (P = 0.15). Metastasis, however, predicted worse outcome (P = 0.0019). We found that adolescent AC and SCC show characteristics similar to such tumors when presenting in adults. Though extremely rare in the adolescent population, these malignant diseases should always be ruled out when young patients present with a short history of dysphagia with signs of clinical deterioration.