Sequential ABT-263 senolytic priming followed by anti-PD-1 checkpoint rescue exploits a temporal immunological window...

IF a sequential senolytic priming and immune checkpoint rescue protocol — ABT-263 (navitoclax, 50 mg/kg oral gavage, 3 days on/4 days off × 3 cycles) followed by a defined 2-week washout and then anti-PD-1 monoclonal antibody (RMP1-14, 200 µg i.p., every 3 days × 6 doses) — is administered to naturally aged female and male C57BL/6 mice (20–24 months), with liver, kidney, lung, and skeletal muscle as primary tissue targets,

THEN the combination will achieve a significantly greater and more durable reduction in p16^INK4a+ and SA-β-galactosidase+ senescent cell burden (≥40% reduction vs. ABT-263 alone, maintained for ≥12 weeks post-treatment) compared to either agent alone, accompanied by measurable improvements in physical function (grip strength, rotarod), systemic inflammatory markers (IL-6, IL-1β plasma), and tissue fibrosis scores,

BECAUSE the following sequential causal chain is operative:

1. Senescent cells accumulate with age and actively kill the immune cells that would normally clear them. Senescent human dermal fibroblasts have been shown to impair anti-tumor immunity by recruiting immune cells into a senescent microenvironment and inducing their death via SASP-mediated mechanisms, creating a self-reinforcing immunosuppressive niche in which clearance capacity progressively collapses (Senescent fibroblasts support tumor growth by inducing immune cell death in humanized models)[https://doi.org/10.1101/2024.06.10.598270].

2. Senescent cells upregulate PD-L1 as an active immune evasion mechanism. Multiple senescent cell populations in aged tissues express elevated surface PD-L1, which engages PD-1 receptors on infiltrating CD8+ T cells, NK cells, and macrophages, suppressing their cytotoxic and phagocytic functions and preventing senescent cell elimination ("The immune checkpoint PD-L1 restricts the clearance of senescent cells during aging", Nature, 2022, referenced in evidence set). In aged C57BL/6 mice (18–24 months), tissue-resident immune cells show hallmarks of exhaustion consistent with chronic PD-L1 engagement.

3. ABT-263 pharmacologically removes the existing immunosuppressive senescent cell mass. By inhibiting Bcl-2, Bcl-xL, and Bcl-w, ABT-263 selectively induces apoptosis in senescent cells that upregulate these SCAPs for survival, reducing p16+ and SA-β-gal+ burden across multiple tissues in aged C57BL/6 mice (evidence set, ABT-263 section). Critically, this cytoreduction dismantles the PD-L1-high, SASP-active senescent cell niche that was actively killing and suppressing immune cells.

4. The washout period allows immune reconstitution in the reduced-immunosuppression environment. Following ABT-263-mediated senescent cell depletion, the acute thrombocytopenic burden of navitoclax subsides (platelets recover within ~2 weeks; evidence set, limitations section), while the reduced local SASP milieu and diminished PD-L1 signaling create a temporal window in which residual or newly recruited NK cells and CD8+ T ...

SENS category: GlycoSENS

Key references: • doi.org/10.1101/2024.06.10.598270]. • doi.org/10.1101/2024.06.10.598270] • doi.org/10.1101/2024.06.10.598270 • doi.org/10.1101/2024.06.10.598270],