Contributions
Abstract: PB2324
Type: Publication Only
Background
Sarcopenia, which is defined as the depletion of skeletal muscle, is associated with unfavorable outcomes in patients with some types of cancer including hematological malignancies. We previously reported that sarcopenia was a poor prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL). However, the mechanism of development of sarcopenia has not been fully understood. Essential amino acid tryptophan is metabolized by indoleamine 2,3-dioxygenase (IDO) via kynurenine pathway. IDO is one of the immunosuppressive factor in tumor microenvironment. IDO was expressed in DLBCL tumor sites, and high IDO expression was a poor prognostic factor.
Aims
We hypothesized that the sarcopenia could be caused by the deficiency of essential amino acid tryptophan.
Methods
We retrospectively analyzed patients with DLBCL who treated in Gifu University Hospital. Skeletal muscle was measured by the analysis of CT images at the L3 level when they were diagnosed. The surface of muscular tissues was selected according to the CT Hounsfield unit. This value was normalized for stature in order to calculate the L3 skeletal muscle index (L3 SMI, cm2/m2). Serum concentrations of tryptophan and tryptophan metabolites, such as kynurenine were measured by HPLC. C2C12 myoblast cells and IDO-expressed lymphoma cell line (Raji-IDO) were used for investigating the effect of IDO on muscle.
Results
The value of L3 SMI was ranged from 27.2 to 52.2 cm2/m2. The levels of serum tryptophan was ranged from 20.2 to 105.7 µM, and serum kynurenine was ranged from 0.678 to 6.78 µM. We found that there was a positive correlation between the value of L3 SMI and the serum tryptophan level in DLBCL patients (p=0.015). These results indicated that tryptophan could be involved in clinically maintaining muscle mass. Therefore, we examined the effect of tryptophan and kynurenine on proliferation and myotube formation of C2C12 myoblast cells. We found that tryptophan depletion and kynurenine supplementation significantly reduced diameter of myotube from 248 to 110 µm and the number of myotube from 24.8 to 3.5 per field during 7 days. Interestingly, the depletion of leucine did not inhibit the proliferation and differentiation of C2C12 cells. Next, C2C12 were co-cultured with Raji cells expressing IDO for 7 days. The proliferation of C2C12 cells were inhibited by IDO-expressing cells, which metabolite tryptophan and produced kynurenines.
Conclusion
Sarcopenia in patients with DLBCL was caused by deficiency of tryptophan, which is metabolized by IDO. The reason why IDO positive DLBCL have poor prognosis might be not only tumor immunosuppression but also sarcopenia. Tryptophan supplementation and IDO inhibitors may prevent sarcopenia and improve the prognosis of DLBCL patients.
Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research
Abstract: PB2324
Type: Publication Only
Background
Sarcopenia, which is defined as the depletion of skeletal muscle, is associated with unfavorable outcomes in patients with some types of cancer including hematological malignancies. We previously reported that sarcopenia was a poor prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL). However, the mechanism of development of sarcopenia has not been fully understood. Essential amino acid tryptophan is metabolized by indoleamine 2,3-dioxygenase (IDO) via kynurenine pathway. IDO is one of the immunosuppressive factor in tumor microenvironment. IDO was expressed in DLBCL tumor sites, and high IDO expression was a poor prognostic factor.
Aims
We hypothesized that the sarcopenia could be caused by the deficiency of essential amino acid tryptophan.
Methods
We retrospectively analyzed patients with DLBCL who treated in Gifu University Hospital. Skeletal muscle was measured by the analysis of CT images at the L3 level when they were diagnosed. The surface of muscular tissues was selected according to the CT Hounsfield unit. This value was normalized for stature in order to calculate the L3 skeletal muscle index (L3 SMI, cm2/m2). Serum concentrations of tryptophan and tryptophan metabolites, such as kynurenine were measured by HPLC. C2C12 myoblast cells and IDO-expressed lymphoma cell line (Raji-IDO) were used for investigating the effect of IDO on muscle.
Results
The value of L3 SMI was ranged from 27.2 to 52.2 cm2/m2. The levels of serum tryptophan was ranged from 20.2 to 105.7 µM, and serum kynurenine was ranged from 0.678 to 6.78 µM. We found that there was a positive correlation between the value of L3 SMI and the serum tryptophan level in DLBCL patients (p=0.015). These results indicated that tryptophan could be involved in clinically maintaining muscle mass. Therefore, we examined the effect of tryptophan and kynurenine on proliferation and myotube formation of C2C12 myoblast cells. We found that tryptophan depletion and kynurenine supplementation significantly reduced diameter of myotube from 248 to 110 µm and the number of myotube from 24.8 to 3.5 per field during 7 days. Interestingly, the depletion of leucine did not inhibit the proliferation and differentiation of C2C12 cells. Next, C2C12 were co-cultured with Raji cells expressing IDO for 7 days. The proliferation of C2C12 cells were inhibited by IDO-expressing cells, which metabolite tryptophan and produced kynurenines.
Conclusion
Sarcopenia in patients with DLBCL was caused by deficiency of tryptophan, which is metabolized by IDO. The reason why IDO positive DLBCL have poor prognosis might be not only tumor immunosuppression but also sarcopenia. Tryptophan supplementation and IDO inhibitors may prevent sarcopenia and improve the prognosis of DLBCL patients.
Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research