Recurrent activating mutations of CD28 in peripheral T-cell lymphomas

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Peripheral T-cell lymphomas (PTCLs) are aggressive cancers with poor prognoses.
• Recent research identified mutations in epigenetic modifiers and RHOA in PTCLs, especially angioimmunoblastic T-cell lymphoma (AITL).
• CD28 is a crucial co-stimulatory receptor for T-cell activation, proliferation, and cytokine production.

Purpose of the Study:

• To investigate the role of CD28 mutations in the pathogenesis of PTCLs.
• To identify specific CD28 mutations and their functional consequences in PTCL development.

Main Methods:

• Genomic analysis to detect mutations in CD28 in PTCL patient samples.
• Surface plasmon resonance assays to measure binding affinities of mutated CD28 to ligands and adaptor proteins.
• Molecular modeling to understand the structural impact of mutations.
• Gene expression analysis and Western blotting to assess downstream signaling pathways.

Main Results:

• Recurrent mutations in CD28 at residues D124 and T195 were identified in 11.3% of AITL cases and one PTCL, not otherwise specified (PTCL-NOS).
• Mutations at D124 increased CD28 binding affinity to CD86, while T195 mutations enhanced binding to adaptor proteins GRB2 and GADS/GRAP2.
• Mutant CD28 (D124V, T195P) expression led to increased transcription of CD28-responsive genes (CD226, TNFA) and enhanced NF-κB activation.

Conclusions:

• CD28 mutations are recurrent in PTCLs, particularly AITL.
• These mutations alter CD28 interactions, leading to increased T-cell signaling and activation.
• Targeting CD28 in mutated PTCLs represents a potential therapeutic strategy.