Abstract
1-methyl-D-tryptophan (1-D-MT) is currently being used in clinical trials in patients with relapsed or refractory solid tumors with the aim of inhibiting indoleamine-2,3-dioxygenase (IDO)-mediated tumor immune escape. IDO is expressed in tumors and tumor-draining lymph nodes and degrades tryptophan (trp) to create an immunsuppressive micromilieu both by depleting trp and by accumulating immunosuppressive metabolites of the kynurenine (kyn) pathway. Here we show that proliferation of alloreactive T-cells cocultured with IDO1-positive human cancer cells paradoxically was inhibited by 1-D-MT. Surprisingly incubation with 1-D-MT increased kyn production of human cancer cells. Cell-free assays revealed that 1-D-MT did not alter IDO1 enzymatic activity. Instead, 1-D-MT induced IDO1 mRNA and protein expression through pathways involving p38 MAPK and JNK signalling. Treatment of cancer patients with 1-D-MT has transcriptional effects that may promote rather than suppress anti-tumor immune escape by increasing IDO1 in the cancer cells. These off-target effects should be carefully analyzed in the ongoing clinical trials with 1-D-MT.
Highlights
In recent years tryptophan degradation has received increasing attention as a potent immunosuppressive mechanism involved in the maintenance of immunological tolerance
We found that 1-D-MT increased IDO1 mRNA and protein in SKOV-3 cells, while IDO2 and TDO remained unaltered (Fig. 5A)
1-D-MT suppressed T cell proliferation when constitutively IDO1-expressing SKOV-3 cells were cocultured with mixed lymphocyte reactions (Fig. 2E,F)
Summary
In recent years tryptophan (trp) degradation has received increasing attention as a potent immunosuppressive mechanism involved in the maintenance of immunological tolerance. IDO-mediated trp degradation is not restricted to tumor cells [7] but is detected in tumor-draining lymph nodes [8]. Some animal experiments demonstrated that IDO1 expression was positively associated with the elimination of malignant cells [18,19]. These findings were corroborated in clinical studies showing that despite being a strong inducer of IDO1, IFN-c was effective in the therapy of ovarian carcinoma and bladder cancer [20,21,22]. In preclinical studies the IDO-inhibitor 1-methyl-tryptophan (1-MT) reduced the tumor volume of mice preimmunized with a tumor antigen [7] and - in combination with chemotherapeutic agents - caused regression of established murine breast cancers [5]. We were interested in the immunomodulatory effects of 1-D-MT in IDO1positive human cancer cells
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