Myeloid-derived suppressor cells attenuate the antitumor efficacy of radiopharmaceutical therapy using 90Y-NM600 in combination with androgen deprivation therapy in murine prostate tumors.

RATIONALE: Androgen deprivation therapy (ADT) is pivotal in treating recurrent prostate cancer and is often combined with external beam radiation therapy (EBRT) for localized disease. However, for metastatic castration-resistant prostate cancer, EBRT is typically only used in the palliative setting, because of the inability to radiate all sites of disease. Systemic radiation treatments that preferentially irradiate cancer cells, known as radiopharmaceutical therapy or targeted radionuclide therapy (TRT), have demonstrable benefits for treating metastatic prostate cancer. Here, we explored the use of a novel TRT, 90Y-NM600, specifically in combination with ADT, in murine prostate tumor models. METHODS: 6-week-old male FVB mice were implanted subcutaneously with Myc-CaP tumor cells and given a single intravenous injection of 90Y-NM600, in combination with ADT (degarelix). The combination and sequence of administration were evaluated for effect on tumor growth and infiltrating immune populations were analyzed by flow cytometry. Sera were assessed to determine treatment effects on cytokine profiles. RESULTS: ADT delivered prior to TRT (ADT→TRT) resulted in significantly greater antitumor response and overall survival than if delivered after TRT (TRT→ADT). Studies conducted in immunodeficient NRG mice failed to show a difference in treatment sequence, suggesting an immunological mechanism. Myeloid-derived suppressor cells (MDSCs) significantly accumulated in tumors following TRT→ADT treatment and retained immune suppressive function. However, CD4+ and CD8+ T cells with an activated and memory phenotype were more prevalent in the ADT→TRT group. Depletion of Gr1+MDSCs led to greater antitumor response following either treatment sequence. Chemotaxis assays suggested that tumor cells secreted chemokines that recruited MDSCs, notably CXCL1 and CXCL2. The use of a selective CXCR2 antagonist, reparixin, further improved antitumor responses and overall survival when used in tumor-bearing mice treated with TRT→ADT. CONCLUSION: The combination of ADT and TRT improved antitumor responses in murine models of prostate cancer, however, this was dependent on the order of administration. This was found to be associated with one treatment sequence leading to an increase in infiltrating MDSCs. Combining treatment with a CXCR2 antagonist improved the antitumor effect of this combination, suggesting a possible approach for treating advanced human prostate cancer.

Interactions and film formation in polyethylenimine-cetyltrimethylammonium bromide aqueous mixtures at low surfactant concentration.

The interactions involved in aqueous mixtures of polyethyleneimine (PEI) and cetyltrimethylammonium bromide (CTAB) were studied under dilute conditions. The phase diagram of this polyelectrolyte-surfactant system of similar charge was constructed by determining the CAC and CMC* values at different PEI concentrations, using surface-tension and conductivity measurements, respectively. Formation of thin films at the air-solution interface was detected at concentrations belonging to the interaction region of the phase diagram, using Brewster angle microscopy. These films were formed at low polymer and surfactant concentrations, 0.01% w/v PEI and 0.1 mmol dm CTAB. Results from SAXS determinations indicate that, under these conditions, mesostructure formation occurs exclusively at the surface. The effect of PEI on surfactant micellisation is determined by the polyelectrolyte nature of the polymer. The presence of the polymer in the aggregate significantly affects free micelle formation, even when hydrophobic interactions are mainly determined by the surfactant structure. The films obtained at low surfactant concentration are mesostructured, composed of five layers, each one 49.7 Å thick, as was determined using specular X-ray reflectometry. These results indicate that mesostructured film formation is achievable under more economical and environmentally friendly conditions, suggesting novel routes for surfactant templating in mixed polyelectrolyte systems of similar charge.