Tryptophan Catabolism Is Associated with Clinical Outcome of Patients with Malignant Lymphoma

Indoleamine 2,3-dioxygenase (IDO) exerts powerful immunomodulatory effects through its enzymatic activity that leads to catabolism of the essential amino acid l-tryptophan. Some metabolites derived from tryptophan generated by IDO such as L-kynurenine, block Ag-driven specific T-cell proliferation and induce T-cell death. Therefore, IDO activity might play an important role in regulation of the immune response exerted by antigen presenting cells and also provide transformed cells with a potent tool to help escape from assault by the immune system. The activity of IDO can be estimated by measuring the serum concentration of l-tryptophan and l-kynurenine. We have previously described that high serum l-kynurenine level is associated with poor prognosis of diffuse large B-cell lymphoma (DLBCL) (Yoshikawa et al. Eur J Hemat 2009). Here, we investigated the tryptophan catabolism in malignant lymphoma.

The study protocol comprised a prospective, consecutive entry design that was approved by our Institutional Review Board. We investigated 163 patients between December 2002 and March 2010 who were histologically diagnosed with malignant lymphoma and 20 healthy adult volunteers. L-tryptophan and l-kynurenine were measured by high performance liquid chromatography. Patients with CD 20 positive NHL received 6 to 8 cycles of either R-CHOP therapy. Each regimen consisted of rituximab, cyclophosphamide, doxorubicin or tetrahydropyranyl-adriamycin, an anthracycline derivative of DOX, vincristine, and prednisolone. Patients with CD 20 negative NHL aged received 6 to 8 cycles of either CHOP therapy. Patients with Hodgkin lymphoma received ABVD therapy. Patients with bulky disease received radiotherapy ranging from 30 to 40 Gy. Some patients with refractory or relapsed NHL who responded to (R)-P-IMVP-16/CBDCA received high-dose chemotherapy followed by autologous stem cell transplantation.

The pathology of underlying comprised Hodgkin lymphoma (n=10), DLBCL (n=75), lymphoblastic lymphoma (LBL, n=3), Burkitt lymphoma (Burkit, n=2), follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=4), mucosa-associated lymphoid tissue lymphoma (MALT, n=14), small lymphocytic lymphoma (SLL, n=2), lymphoplasmacytic lymphoma (LPL, n=4), anaplastic large cell lymphoma (ALCL, n=4), peripheral T-cell lymphoma, unspecified (PTCL-U, n=13), and NK/T cell lymphoma (NK/T, n= 4). The median serum l-kynurenine levels in patients (2.29 ± 4.97 mM) were significantly higher than in healthy volunteers (1.13 ± 0.32 mM). The ratio of l-kynurenine/l-tryptophan levels in patients with ML (0.040 ± 0.487) was significantly higher than in healthy volunteers (0.022 ± 0.009). We found no significant correlations between l-kynurenine or l-tryptophan and lymphoma histology. Regardless of the pathologic classification, median l-kynurenine levels in lymphoma patients were higher than in healthy volunteers. We established the cut-off value of l-kynurenine at 2.2 mM which was essentially the median for all patients. In the aggressive B cell lymphoma patients (DLBCL, Burkit, and LBL, n=81), the 3-year OS rates with l-kynurenine < 2.2 mM and ≥ 2.2 mM were 69.5% and 43.6%, respectively (P <0.05). While, in the indolent B cell lymphoma patients (FL, MALT, MCL, LPL and SLL, n=51), the 3-year OS rates with l-kynurenine < 2.2 mM and ≥ 2.2 mM were 95% and 90.6%, respectively (N.S). In the T cell lymphoma patients (ALCL, PTCL, and NK/T n=21), the 3-year OS rates with l-kynurenine < 2.2 mM and ≥ 2.2 mM were 75% and 55.2%, respectively (N.S).

Serum l-kynurenine was a significant predictor for the survival of aggressive B cell lymphoma patients. The increase in serum l-kynurenine levels is thought to be caused by enhanced l-tryptophan catabolism, which inhibits tumoral local immunity. The result of a poor prognosis among patients with high l-kynurenine levels indicates that depressed local immunity due to enhanced IDO activity contributes to becoming refractory to treatment.

No relevant conflicts of interest to declare.