For patients with higher-risk myelodysplastic syndromes (MDS), immunomodulator indoleamine-2,3-dioxygenase (IDO-1) may be a promising predictor of treatment outcome with hypomethylating agents (HMAs), such as azacitidine (AZA), and a potential therapeutic target, according to study results published in the British Journal of Haematology.

Catharina Müller-Thomas, MD, of the department of medicine I, hematology and oncology at München Klinik Schwabing in Germany, and colleagues aimed to determine the prognostic value of IDO-1 by assessing its expression in the bone marrow of patients with higher-risk MDS who were treated with HMAs. Patients with higher-risk MDS, secondary acute myeloid leukemia (sAML), or MDS/myeloproliferative neoplasms (MPN) who were treated at the Technische Universität München and Heinrich-Heine Universität Düsseldorf from 2004 to 2013 were enrolled in the study. The researchers also used human MDS cell lines SKK-1 and MDS-L to confirm the immunoregulatory functions of IDO-1 in vitro.

A total of 95 patients (median age, 71 years) were included the study; 61 patients had MDS, 28 patients had sAML, and 6 had MDS/MPN. Patients were classified according to cytogenetic risk groups: very low-risk karyotype (0 patients), good-risk karyotype (9 patients), intermediate-risk karyotype (15 patients), poor-risk karyotype (20 patients), and very poor-risk karyotype (31 patients).

Of patients with higher-risk MDS, 37% had moderate-to-strong cytoplasmic IDO-1 expression, while 63% had negative or weak expression. Positivity of IDO-1 was predictive of both AZA treatment failure (48% for IDO-1 vs 83% for IDO-1+; P <.001) and shorter overall survival (21.4 months for IDO-1vs 10.8 months for IDO-1+; hazard [HR], 0.615; P =.034).

Additionally, IDO-1 expression in the patient samples was negatively correlated with the CD8/CD3 ratio (R2=0.71; P <.0001), suggesting an immunosuppressive role of IDO-1.

Fifteen patients (5 IDO-1+ patients, 10 IDO-1patients) who had undergone bone marrow biopsies during AZA treatment were identified, which allowed the investigators to compare CD8+ T cell response before and after/during AZA treatment at 8 weeks, 16 weeks, and 32 weeks. The IDO-1patients showed a clear increase in CD8+ T cells, whereas IDO-1+ patients showed nearly no increase at all (all weeks, P <.001). This was suggestive of tryptophan starvation that stops CD8+ T cell proliferation.

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To assess the effect of tryptophan starvation on CD8+ T cell proliferation, the team conducted in vitro experiments with IDO-1+ MDS cell lines and showed that tryptophan depletion from the medium resulted in a significant reduction of relative proliferation of the cells to 20% to 25%. Adding tryptophan to the medium rescued T cell proliferation to nearly 100%. The authors suggested that these results indicate that IDO-1 expression induces an immunosuppressive microenvironment in MDS, which could lead to treatment failure with AZA treatment.

“IDO-1 positivity in the bone marrow might be useful for identifying patients with a low probability of achieving clinical benefit from HMA,” the authors wrote. “In addition, our data further distinguish IDO-1 as an emerging promising target, especially for combination therapies with HMA in patients with higher-risk MDS,” concluded the authors.

Reference

Müller‐Thomas C, Heider M, Piontek G, et al. Prognostic value of indoleamine 2,3 dioxygenase in patients with higher‐risk myelodysplastic syndromes treated with azacytidine [published online April 29, 2020]. Br J Haematol. doi: 10.1111/bjh.16652