Senescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Cellular senescence is a stress-induced state impacting aging, cancer development, and therapy response.
• Senescent cells undergo significant chromatin remodeling and transcriptional changes.
• Therapy-induced senescence (TIS) in B-cell lymphoma involves complex cellular reprogramming.

Purpose of the Study:

• To investigate myeloid-skewed aberrant lineage plasticity in therapy-induced senescence (TIS) of B-cell lymphoma.
• To explore the immunological consequences of this plasticity.
• To determine the prognostic and therapeutic implications of TIS-related myeloid plasticity in lymphoma.

Main Methods:

• Analysis of primary human and murine B-cell lymphoma undergoing TIS.
• Identification of enriched transcription factor (TF) networks (AP-1, C/EBPβ, PU.1) in TIS cells.
• Assessment of monocytic-dendritic cell (DC) differentiation properties in TIS lymphoma cells.
• In vitro T-cell mediated lysis assays and in vivo tumor-free survival studies in mice.
• Analysis of diffuse large B-cell lymphoma patient data for TIS-related DC signatures.

Main Results:

• TIS lymphoma cells exhibit enrichment of myeloid TF networks, unlike chemotherapy-exposed senescence-incapable cells.
• TIS lymphoma cells display lineage plasticity, adopting monocytic-dendritic cell (DC) differentiation characteristics.
• TIS lymphoma cells are more susceptible to T-cell lysis in vitro.
• Mice with DC-skewed Eμ-myc lymphoma show prolonged tumor-free survival.
• High expression of a TIS-related DC signature correlates with superior long-term outcomes in diffuse large B-cell lymphoma patients.

Conclusions:

• Senescence-dependent aberrant myeloid plasticity in B-cell lymphoma is a key mechanism driving immunogenic reprogramming.
• This plasticity, characterized by DC differentiation, enhances anti-tumor immunity.
• The findings reveal a therapeutically exploitable and prognostically favorable role for senescence in lymphoma.