Abstract
This study investigated the impact of immune-related pathway inhibition, among them indolamine 2,3-dioxygenase (IDO), alone and together with immune cells on growth and viability of colorectal cancer (CRC) cells. A panel of patient-derived CRC cell lines with different molecular characteristics (CpG island methylator phenotype, chromosomal, and microsatellite instability) was included. Initial phenotyping of CRC cell lines (n=17) revealed high abundance of immunosuppressive checkpoint-molecules in general, but an individual profile for IDO. Presence of immune-related molecules was independent of the molecular subtype. Selective treatment of CRC cell lines showing high or low IDO expression (n=2 cell lines each) was performed with single agents and combinations of Indoximod, Curcumin, and Gemcitabine with and without the addition of peripheral blood lymphocytes (PBL) in an allogeneic setting. All substances affected CRC cell growth in a cell line specific manner. The combination of Curcumin and Gemcitabine proved to be most effective in tumor cell elimination. Functional read-out analyses identified cellular senescence, after both single and combined treatment. Curcumin alone exerted strong cytotoxic effects by inducing early and late apoptosis. Necrosis was not detectable at all. Addition of lymphocytes generally boosted antitumoral effects of all IDO-inhibitors, with up to 80 % cytotoxicity for the Curcumin treatment. Here, no obvious differences became apparent between individual cell lines. Combined application of Curcumin and low-dose chemotherapy is a promising strategy to kill tumor target cells and to stimulate antitumoral immune responses.
Highlights
Immune-checkpoint inhibitors constitute one of the most promising novel therapeutic approaches for cancer [1]
Three molecular pathways have been implicated in colorectal tumorigenesis: chromosomal instability (CIN, ∼60 %), CpG island methylator phenotype (CIMP, ∼30 %), and microsatellite instability (MSI, ∼15 %)
With the known toxic side effects of Gemcitabine, our findings argue in favor of Curcumin for further development of combinatorial treatment strategies
Summary
Immune-checkpoint inhibitors constitute one of the most promising novel therapeutic approaches for cancer [1]. These molecules reconstitute the hosts’ antitumoral immune response by interrupting tumor-induced tolerance and are at the forefront of immunotherapy development. Three molecular pathways have been implicated in colorectal tumorigenesis: chromosomal instability (CIN, ∼60 %), CpG island methylator phenotype (CIMP, ∼30 %), and microsatellite instability (MSI, ∼15 %). This latter subgroup is more likely to respond to immunotherapy [3]. To downregulate major histocompatibility complex (MHC) class I on the tumor cells’ surface and inactivation of the antigen-processing machinery, upregulation of immune-checkpoint-molecules (such as BioMed Research International programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1(PD-L1)) represents another escape mechanism [4]
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