Correlative Monitoring of Immune Activation and Tissue Damage in Malignant Melanoma-An Algorithm for Identification of Tolerance Breakage During Immune Checkpoint Inhibitor Therapy of Cancer.

We describe an innovative approach for identification of tolerance breakage during immune checkpoint inhibitor therapy in malignant melanoma. Checkpoint inhibitor therapy enhances the immunologic clearance of cancer by suppressing pathways which induce immune suppression and tolerance. We posit that by analyzing temporal correlations of key markers of immune activation and tissue damage it would be possible to detect the onset of anticancer immune reaction as well as of immunologic adverse effects which might become crucial for optimization as well as safety of immune checkpoint inhibitor treatment. We analyzed time courses of routine laboratory values of serum tumor markers as well as of markers of immune activation in 17 patients with metastasized malignant melanoma receiving checkpoint inhibition and weekly laboratory controls. A parallel serum level increase of interleukin-6 and the tumor marker S100B could be identified in 13 patients, suggesting that the onset of tolerance breakage under checkpoint inhibition may be identified and measured. Immune-related adverse events in the patients were also accompanied by a peak of IL-6. In six patients, the onset of a putative anticancer immune reaction and the beginning of immunologic adverse events occurred in the same treatment cycle; in six patients the immunologic adverse reactions took place in separate cycles.

Melanoma stem cell maintenance and chemo-resistance are mediated by CD133 signal to PI3K-dependent pathways.

Melanoma stem cells (MSCs) are characterized by their unique cell surface proteins and aberrant signaling pathways. These stemness properties are either in a causal or consequential relationship to melanoma progression, treatment resistance and recurrence. The functional analysis of CD133+ and CD133- cells in vitro and in vivo revealed that melanoma progression and treatment resistance are the consequences of CD133 signal to PI3K pathway. CD133 signal to PI3K pathway drives two downstream pathways, the PI3K/Akt/MDM2 and the PI3K/Akt/MKP-1 pathways. Activation of PI3K/Akt/MDM2 pathway results in the destabilization of p53 protein, while the activation of PI3K/Akt/MKP-1 pathway results in the inhibition of mitogen-activated protein kinases (MAPKs) JNK and p38. Activation of both pathways leads to the inhibition of fotemustine-induced apoptosis. Thus, the disruption of CD133 signal to PI3K pathway is essential to overcome Melanoma resistance to fotemustine. The pre-clinical verification of in vitro data using xenograft mouse model of MSCs confirmed the clinical relevance of CD133 signal as a therapeutic target for melanoma treatment. In conclusion, our study provides an insight into the mechanisms regulating MSCs growth and chemo-resistance and suggested a clinically relevant approach for melanoma treatment.

Tumor necrosis factor-α triggers opposing signals in head and neck squamous cell carcinoma and induces apoptosis via mitochondrial- and non-mitochondrial-dependent pathways.

Head and neck squamous cell carcinoma (HNSCC) remains one of the most common malignancies worldwide. Although the treatment outcomes of HNSCC have improved in recent years, the prognosis of patients with advanced-stage disease remains poor. Current treatment strategies for HNSCC include surgery as a primary therapy, while radio-, chemo-, and biotherapeutics can be applied as second-line therapy. Although tumor necrosis factor-α (TNF-α) is a potent tumor suppressor cytokine, the stimulation of opposing signals impairs its clinical utility as an anticancer agent. The aim of this study was to elucidate the mechanisms regulating TNF-α­induced opposing signals and their biological consequences in HNSCC cell lines. We determined the molecular mechanisms of TNF-α-induced opposing signals in HNSCC cells. Our in vitro analysis indicated that one of these signals triggers apoptosis, while the other induces both apoptosis and cell survival. The TNF-α-induced survival of HNSCC cells is mediated by the TNF receptor-associated factor 2 (TRAF2)/nuclear factor (NF)-κB-dependent pathway, while TNF-α-induced apoptosis is mediated by mitochondrial and non-mitochondrial-dependent mechanisms through FADD-caspase-8-caspase-3 and ASK-JNK-p53-Noxa pathways. The localization of Noxa protein to both the mitochondria and endoplasmic reticulum (ER) was found to cause mitochondrial dysregulation and ER stress, respectively. Using inhibitory experiments, we demonstrated that the FADD­caspase-8­caspase-3 pathway, together with mitochondrial dysregulation and ER stress-dependent pathways, are essential for the modulation of apoptosis, and the NF-κB pathway is essential for the modulation of anti-apoptotic effects/cell survival during the exposure of HNSCC cells to TNF-α. Our data provide insight into the mechanisms of TNF-α-induced opposing signals in HNSCC cells and may further help in the development of novel therapeutic approaches with which to minimize the systemic toxicity of TNF-α.

Cutaneous Basal Cell Carcinoma with Lymph Node and Pulmonary Metastases.

Basal cell carcinoma (BCC) is the most common skin cancer. Metastatic BCC is an extraordinary rare finding observed in only 0.5% of all cases. Until the introduction of the small molecule hedgehog inhibitor vismodegib, patients with metastatic BCC were treated with chemotherapy, most frequently platinum-based with mixed responses to therapy. We present the case of a 55-year-old Caucasian man who suffered from BCC on his left arm with lymph node and pulmonary metastases. Sonic hedgehog blockade with vismodegib only induced a short remission, and the patient succumbed to the cancer.