Increased mTORC2 pathway activation in lymph nodes of iMCD-TAFRO

Area of Science:

• Hematology
• Oncology
• Cell Signaling

Background:

• Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening hematologic disorder characterized by excessive cytokine production, notably interleukin-6 (IL-6).
• While IL-6 inhibition benefits some patients, a subset remains refractory, necessitating exploration of alternative therapeutic targets.
• The mechanistic target of rapamycin (mTOR) pathway, comprising mTORC1 and mTORC2, has emerged as a potential therapeutic avenue.

Purpose of the Study:

• To investigate the role and activation status of mTORC2 signaling in iMCD.
• To compare mTORC2 activation in iMCD subtypes, including iMCD-TAFRO and iMCD-not-otherwise-specified (iMCD-NOS).
• To evaluate the potential of dual mTORC1/mTORC2 inhibition as a therapeutic strategy for iMCD.

Main Methods:

• Quantification of the mTORC2 effector protein pNDRG1 via immunohistochemistry on lymph node biopsies.
• Analysis included patients with iMCD-TAFRO, iMCD-NOS, and control subjects.
• Comparison of pNDRG1 expression in iMCD-TAFRO germinal centers with autoimmune lymphoproliferative syndrome (ALPS).

Main Results:

• Elevated mTORC2 activation, indicated by increased pNDRG1, was observed in iMCD-TAFRO lymph nodes and iMCD-NOS interfollicular spaces compared to controls.
• Increased pNDRG1 expression in iMCD-TAFRO germinal centers was noted relative to ALPS.
• pNDRG1 staining was comparable between iMCD-NOS and ALPS.

Conclusions:

• These findings indicate heightened mTORC2 activity in iMCD.
• The results support the rationale for exploring dual mTORC1/mTORC2 inhibitors for iMCD treatment, particularly for patients unresponsive to current therapies.
• Further research into mTOR pathway modulation in iMCD is warranted.