ABSTRACT
Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment (TME) induces immune dysfunctional tumor-infiltrating DCs (TIDCs), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we report that fatty acid-carrying tumor-derived exosomes (TDEs) induce immune dysfunctional DCs to promote immune evasion. Mechanistically, peroxisome proliferator activated receptor (PPAR) α responds to the fatty acids delivered by TDEs, resulting in excess lipid droplet biogenesis and enhanced fatty acid oxidation (FAO), culminating in a metabolic shift toward mitochondrial oxidative phosphorylation, which drives DC immune dysfunction. Genetic depletion or pharmacologic inhibition of PPARα effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARα lies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target.
Subject(s)
Dendritic Cells/physiology , PPAR alpha/metabolism , Animals , Cell Line , Cells, Cultured , Dendritic Cells/immunology , Fatty Acids/metabolism , Female , Humans , Lipid Metabolism , Lipids , Liver/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/metabolism , Oxidation-Reduction , Oxidative Phosphorylation , PPAR alpha/physiologyABSTRACT
A new series of water-soluble, mononaphthotrisulfobenzoporphyrazines, bearing an alkynyl side chain of varying lengths on the naphtho ring, were prepared and tested for their efficacy to inhibit plasma extravasation when used as photosensitizers during photodynamic therapy (PDT) of the retina in the rat. The hexynyl substituted photosensitizer was the most potent, and was able to produce complete inhibition, at low doses of photosensitizer and light.
Subject(s)
Papilledema/drug therapy , Photosensitizing Agents/chemistry , Photosensitizing Agents/therapeutic use , Porphyrins/chemistry , Porphyrins/therapeutic use , Animals , Extravasation of Diagnostic and Therapeutic Materials/drug therapy , Papilledema/blood , Photochemotherapy , Rats , Solubility , Structure-Activity Relationship , Water/chemistryABSTRACT
To identify optimal features of metalated sulfophthalocyanine dyes for their use as photosensitizers in the photodynamic therapy of cancer, we synthesized a series of alkynyl-substituted trisulfonated phthalocyanines and compared their amphiphilic properties to a number of parameters related to their photodynamic potency. Varying the length of the substituted alkynyl side-chain modulates the hydrophobic/hydrophilic properties of the dyes providing a linear relationship between their n-octanol/water partition coefficients and retention times on reversed-phase HPLC. Aggregate formation of the dyes in aqueous solution increased with increasing hydrophobicity while monomer formation was favored by the addition of serum proteins or organic solvent. Trisulfonated zinc phthalocyanines bearing hexynyl and nonynyl substituents exhibited high cellular uptake with strong localization at the mitochondrial membranes, which coincided with effective photocytotoxicity toward EMT-6 murine mammary tumor cells. Further increase in the length of the alkynyl chains (dodecynyl, hexadecynyl) did not improve their phototoxicity, likely resulting from extensive aggregation of the dyes in aqueous medium and reduced cell uptake. Aggregation was evident from shifts in the electronic spectra and reduced capacity to generate singlet oxygen. When monomerized through the addition of Cremophor EL all sulfonated zinc phthalocyanines gave similar singlet oxygen yields. Accordingly, differences in the tendency of the dyes to aggregate do not appear to be a determining factor in their photodynamic potency. Our results confirm that the latter in particular relates to their amphiphilic properties, which facilitate cell uptake and intracellular localization at photosensitive sites such as the mitochondria. Combined, these factors play a significant role in the overall photodynamic potency of the dyes.
Subject(s)
Glycerol/analogs & derivatives , Photochemotherapy , Photosensitizing Agents/chemistry , Sulfadiazine/chemistry , Sulfamerazine/chemistry , Sulfathiazoles/chemistry , Animals , Chromatography, High Pressure Liquid , Coloring Agents/chemical synthesis , Coloring Agents/metabolism , Coloring Agents/therapeutic use , Dermatitis, Phototoxic , Glycerol/chemistry , Glycerol/pharmacology , Hydrophobic and Hydrophilic Interactions , Indoles/chemical synthesis , Indoles/metabolism , Indoles/therapeutic use , Isoindoles , Mammary Neoplasms, Animal , Mice , Organometallic Compounds/chemical synthesis , Organometallic Compounds/metabolism , Organometallic Compounds/therapeutic use , Oxidation-Reduction , Photolysis , Photosensitizing Agents/therapeutic use , Structure-Activity Relationship , Tryptophan/chemistry , Tryptophan/metabolism , Tumor Cells, Cultured , Water/chemistry , Zinc CompoundsABSTRACT
Phthalocyanine-based photosensitizers, coupled via a 17alpha-ethynyl group to estradiol using Pd(II) as a catalyst, were synthesized and evaluated for their estrogen receptor binding affinity and in vitro photocytotoxicity. The highest receptor binding affinities (RBA=8-13) were observed with lipophilic conjugates coupled via a relative long spacer group while the sulfonated analogues showed little binding affinities (RBA <2). The highest photocytotoxicity was observed with the sulfonated conjugates, the nature of the spacer group did not have a pronounced effect.
