Nanomedicine and cancer immunotherapy: focus on indoleamine 2,3-dioxygenase inhibitors

Abstract

Nanomedicine application in cancer immunotherapy is currently one of the most challenging areas in cancer therapeutic intervention. Innovative solutions have been provided by nanotechnology to deliver cytotoxic agents to the cancer cells partially affecting the healthy cells of the body during the process. Nanoparticle-based drug delivery is an emerging approach to stimulate the immune responses against cancer. The inhibition of indoleamine 2,3-dioxygenase (IDO) is a pivotal area of research in cancer immunotherapy. IDO is a heme-containing immunosuppressive enzyme, which is responsible for the degradation of tryptophan while increasing the concentration of kynurenine metabolites. Various preclinical studies showed that IDO inhibition in certain diseases may result in significant therapeutic effects. Here, we provide a review of the natural and synthetic inhibitors of IDO. These inhibitors are classified according to their source, inhibitory concentrations, the chemical structure, and the mechanism of action. Tumor-targeted chemotherapy is an advanced technique and has more advantages as compared to the conventional chemotherapy. Search for more efficient and less toxic nanoparticles in conjunction with compounds to inhibit IDO is still an area of interest for several research groups worldwide, especially revealing to be an extensive and a promising area in cancer therapeutic innovations.

How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive

“…The interference with MSC-mediated immunosuppressive molecular mechanisms, obtained using specific inhibitory drugs, is an additional mean by which the immune escape favored by tumor MSC can be avoided ( 1 – 4 ). In this context, all the inhibitors already used in therapeutic schemes to block IDO, HO, ARGI and II, NOS2, PGE 2 , and TGF-β activity can be employed to reduce MSC influence on tumor cell growth ( 211 – 217 ) (Figure 3 ). In this context, the immune check point inhibitors anti-PD1 and/or PDL-1 huAb can have an important role ( 132 , 137 , 218 – 220 ).…”

<p>Lipid nanobubbles as an ultrasound-triggered artesunate delivery system for imaging-guided, tumor-targeted chemotherapy</p>

“…Their stability is due to PEG and lipid encapsulation, which can also improve the poor water solubility of loaded Arte (Figure 1A). In addition, PEG, as a surfactant, can form a water barrier on the surface of the phospholipid membrane and prolong the retention time in the blood circulation 22–24Figure 2F shows the UV-Vis spectra of FA-ALNBs, which exhibited absorbance peak similar to Arte at wavelengths of 280 nm, demonstrating the existence of Arte in FA-ALNBs.…”

The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy

“…Bona fide transcription factor binding sites have been detected by ChIP-seq for a large catalog of human transcription factors ( 3 ). The identified gene regulatory proteins involve (i) NF- κB, which allows IDO1 mRNA expression regulation through the interferon pathway ( 6 ), (ii) the aryl hydrocarbon receptor (AhR) that binds to putative dendritic-cell responsive elements and promotes the l -Kyn-dependent induction of IDO1 ( 7 , 8 ), and (iii) CTCF that mediates IDO1 expression via long-range chromatin looping interactions between the promoter and distal enhancer regions ( 9 ).…”

“…Indoleamine-2,3-dioxygenase1 production is elevated upon (i) IFN-γ production of effector T cells ( 2 ), (ii) inflammatory cytokine production of innate immune cells ( 6 , 38 ), (iii) IL-10 and IL-27 stimulation ( 39 ), (iv) CTLA4 expression on Treg cells causing increased IDO1 secretion by dendritic cells (DCs) ( 40 ), and (v) TGF-β, IL-10 and adenosine production of Treg and other immunosuppressive cells ( 40 – 42 ), (vi) cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) stimuli that are mediated through the PKC, PI3K, and MAPK pathways (several types of tumors carry PI3K or MAPK oncogenic mutations leading to constitutive IDO1 expression.) ( 43 ).…”