Cisplatin inhibits frequency and suppressive activity of monocytic myeloid-derived suppressor cells in cancer patients.

Cancer immunotherapies have induced long-lasting responses in cancer patients including those with melanoma and head and neck squamous cell carcinoma (HNSCC). However, the majority of treated patients does not achieve clinical benefit from immunotherapy because of systemic tumor-induced immunosuppression. Monocytic myeloid-derived suppressor cells (M-MDSCs) are implicated as key players in inhibiting anti-tumor immune responses and their frequencies are closely associated with tumor progression.

Autologous monocyte-derived DC vaccination combined with cisplatin in stage III and IV melanoma patients: a prospective, randomized phase 2 trial.

Background: Autologous dendritic cell (DC) vaccines can induce tumor-specific T cells, but their effect can be counteracted by immunosuppressive mechanisms. Cisplatin has shown immunomodulatory effects in vivo which may enhance efficacy of DC vaccination.

Methods: This is a prospective, randomized, open-label phase 2 study (NCT02285413) including stage III and IV melanoma patients receiving 3 biweekly vaccinations of gp100 and tyrosinase mRNA-loaded monocyte-derived DCs with or without cisplatin.

STAT Family Protein Expression and Phosphorylation State during moDC Development Is Altered by Platinum-Based Chemotherapeutics.

The STAT signaling pathway is important in dendritic cell (DC) development and function. Tumor cells can induce STAT signaling, thereby inhibiting DC maturation and immunostimulatory functions, leading to hampered efficacy of DC-based immunotherapies. Platinum-based chemotherapeutics can inhibit STAT signaling, thereby making them an interesting tool to improve DC development and function.

Direct inhibition of STAT signaling by platinum drugs contributes to their anti-cancer activity.

Platinum-based chemotherapeutics are amongst the most powerful anti-cancer drugs. Although their exact mechanism of action is not well understood, it is thought to be mediated through covalent DNA binding. We investigated the effect of platinum-based chemotherapeutics on signaling through signal transducer and activator of transcription (STAT) proteins, which are involved in many oncogenic signaling pathways.

Monitoring of dynamic changes in Keyhole Limpet Hemocyanin (KLH)-specific B cells in KLH-vaccinated cancer patients.

Keyhole limpet hemocyanin (KLH) is used as an immunogenic neo-antigen for various clinical applications and during vaccine development. For advanced monitoring of KLH-based interventions, we developed a flow cytometry-based assay for the ex vivo detection, phenotyping and isolation of KLH-specific B cells. As proof-of-principle, we analyzed 10 melanoma patients exposed to KLH during anti-cancer dendritic cell vaccination.

Human CD1c(+) DCs are critical cellular mediators of immune responses induced by immunogenic cell death.

Chemotherapeutics, including the platinum compounds oxaliplatin (OXP) and cisplatin (CDDP), are standard care of treatment for cancer. Although chemotherapy has long been considered immunosuppressive, evidence now suggests that certain cytotoxic agents can efficiently stimulate antitumor responses, through the induction of a form of apoptosis, called immunogenic cell death (ICD). ICD is characterized by exposure of calreticulin and heat shock proteins (HSPs), secretion of ATP and release of high-mobility group box 1 (HMGB1).

Improving cancer immunotherapy by targeting the STATe of MDSCs.

Cancer immunotherapy is a promising therapeutic avenue; however, in practice its efficacy is hampered by an immunosuppressive tumor microenvironment that consists of suppressive cell types like myeloid-derived suppressor cells (MDSCs). Eradication or reprogramming of MDSCs could therefore enhance clinical responses to immunotherapy. Here, we review clinically available drugs that target MDSCs, often through inhibition of STAT signaling, which is essential for MDSC accumulation and suppressive functions.

Preclinical exploration of combining plasmacytoid and myeloid dendritic cell vaccination with BRAF inhibition.

Background: Melanoma is the most lethal type of skin cancer and its incidence is progressively increasing. The introductions of immunotherapy and targeted therapies have tremendously improved the treatment of melanoma. Selective inhibition of BRAF by vemurafenib results in objective clinical responses in around 50 % of patients suffering from BRAFV600 mutated melanoma.