Abstract
Immune escape is an early phenomenon in cancer development/progression. Indoleamine 2,3-dioxygenase 1 (IDO1) is a normal endogenous mechanism of acquired peripheral immune tolerance and may therefore be tumor-promoting. This study investigated the clinical relevance of IDO1 expression by immune cells in the lymph nodes and blood and of the serum kynurenine/tryptophan (Kyn/Trp) ratio in 65 systemic treatment naïve stage I-III melanoma patients. Blood samples were collected within the first year of diagnosis. Patients had a median follow-up of 61 months. High basal IDO1 expression in peripheral monocytes and low IFNγ-induced IDO1 upregulation correlated with worse outcome independent from disease stage. Interestingly studied factors were not interrelated. During follow-up, the risk of relapse was 9% (2/22) in the subgroup with high IFNγ-induced IDO1 upregulation in monocytes. In contrast, if IDO1 upregulation was low, relapse occurred in 30% (3/10) of patients with low basal IDO1 expression in monocytes and in 61.5% (8/13) in the subgroup with high basal IDO1 expression in monocytes (Log-Rank test, p=0.008). This study reveals some immune features in the blood of early stage melanoma that may be of relevance for disease outcome. These may offer a target for sub-stratification and early intervention.
Highlights
The incidence of cutaneous melanoma increases worldwide and is responsible for 75% of skin cancerrelated deaths [1]
In stage I-III, the Kyn levels and the Kyn/Trp ratio were significantly higher in males compares to females whereas only a trend to higher Trp concentrations in males was noticed (p=0.061)
IDO1 shift varied across patients and a simultaneous upregulation of programmed death-ligand 1 (PD-L1) was observed in both monocyte subsets. As this shift was clearly heterogeneous across patients, we investigated whether the interferon gamma (IFNg)-induced IDO1 upregulation in CD14+ monocytes was associated with clinical outcome
Summary
The incidence of cutaneous melanoma increases worldwide and is responsible for 75% of skin cancerrelated deaths [1]. New insights in immuno-oncology and the subsequently developed immunotherapies have caused a major breakthrough in the oncology field in general and in the management of metastatic melanoma in the last decade, creating the hope of curing (metastatic) cancer. The interaction between the tumor and the host immune system is acknowledged as one of the hallmarks of cancer development and progression [12]. Studies in early stage cancer demonstrated that tumors harness various mechanisms to escape immune surveillance during their evolution [13, 14]. Immune evasion through upregulation of immune checkpoints such as indoleamine 2,3-dioxygenase (IDO1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-ligand 1 (PD-L1) has been identified as an evolutionary trajectory during pre-invasive stages of lung cancer [15]
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