Therapy-induced senescent cancer cells exhibit complement activation and increased complement regulatory protein...

Area of Science:

• Cancer Biology
• Immunology
• Cellular Senescence

Background:

• Therapy-induced senescence (TIS) is a key chemotherapy response, potentially leading to immune evasion.
• The complement system's role in anti-cancer immunity is known, but its interaction with senescent tumor cells is unclear.

Purpose of the Study:

• To investigate the role of the complement system in the immune response to therapy-induced senescent (TIS) cancer cells.
• To explore complement activation and protein expression in TIS cancer cell lines and patient samples.

Main Methods:

• Induced TIS in lung, breast, and pancreatic cancer cell lines using etoposide or doxorubicin.
• Assessed TIS markers (morphology, β-galactosidase, p21^Cip1, lamin B1).
• Investigated complement activation (C5b-9 deposition), protein expression (CD59, factor H, C3), and secretion using microscopy, qPCR, ELISA, and in silico analysis.

Main Results:

• TIS induced terminal complement pathway activation (C5b-9 deposition) on senescent cells.
• Upregulation of complement regulatory proteins CD59 and factor H was observed.
• Increased C3 expression and secretion into the medium occurred in A549 cells; elevated C3 was also found in patient samples.

Conclusions:

• Therapy-induced senescence triggers complement activation and upregulates complement regulatory proteins.
• Increased C3 expression in senescent cells suggests a role for complement in modulating the tumor microenvironment post-senescence induction.
• Findings highlight complement's involvement in the response to chemotherapy-induced cellular senescence.