Senescent cells re‐engineered to express soluble programmed death receptor‐1 for inhibiting programmed death receptor‐1/programmed death ligand‐1 as a vaccination approach against breast cancer

Abstract

Various types of vaccines have been proposed as approaches for prevention or delay of the onset of cancer by boosting the endogenous immune system. We previously developed a senescent‐cell‐based vaccine, induced by radiation and veliparib, as a preventive and therapeutic tool against triple‐negative breast cancer. However, the programmed death receptor‐1/programmed death ligand‐1 (PD‐1/PD‐L1) pathway was found to play an important role in vaccine failure. Hence, we further developed soluble programmed death receptor‐1 (sPD1)‐expressing senescent cells to overcome PD‐L1/PD‐1‐mediated immune suppression while vaccinating to promote dendritic cell (DC) maturity, thereby amplifying T‐cell activation. In the present study, sPD1‐expressing senescent cells showed a particularly active status characterized by growth arrest and modified immunostimulatory cytokine secretion in vitro. As expected, sPD1‐expressing senescent tumor cell vaccine (STCV/sPD‐1) treatment attracted more mature DC and fewer exhausted‐PD1+ T cells in vivo. During the course of the vaccine studies, we observed greater safety and efficacy for STCV/sPD‐1 than for control treatments. STCV/sPD‐1 pre‐injections provided complete protection from 4T1 tumor challenge in mice. Additionally, the in vivo therapeutic study of mice with s.c. 4T1 tumor showed that STCV/sPD‐1 vaccination delayed tumorigenesis and suppressed tumor progression at early stages. These results showed that STCV/sPD‐1 effectively induced a strong antitumor immune response against cancer and suggested that it might be a potential strategy for TNBC prevention.

Senolytic drugs: from discovery to translation

“…Several other strategies have recently been used to develop potentially senolytic interventions. These include the development of galacto-oligosaccharide-coated nanoparticles with toxic cargos that are engulfed by senescent cells and opened by SA-b-gal, vaccines and immunomodulators [10,[98][99][100]. Perhaps some of these will make it through preclinical studies and into clinical trials within the next few years.…”

Soluble PD-1: Predictive, Prognostic, and Therapeutic Value for Cancer Immunotherapy

“…Recently, senescent cells were used as vaccines as these cells cannot proliferate but still remains metabolically active (184,185). Accumulation of senescent cells with various SASP (senescence-associated secretory phenotype) could cause proinflammatory microenvironments (185).…”

Analysis of Plasma EBV-DNA and Soluble Checkpoint Proteins in Nasopharyngeal Carcinoma Patients after Definitive Intensity-Modulated Radiotherapy

“…Preclinical studies hypothesized that sPD-1 blocks the regulatory properties of PD-1/PD-L1, followed by restoration of T cell function, and proliferation and enhancement of immune-mediated tumor control [8]. Mice transfected with sPD-1 showed a strong antitumor immune response with delayed tumorigenesis and suppressed and regressed tumor progression [21, 22].…”