The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients’ Lymphocytes Favoring Chemotherapy Efficacy

Abstract

Glioblastoma (GBM) is the most common primary brain cancer with the median age at diagnosis around 64 years, thus pointing to aging as an important risk factor. Indeed, aging, by increasing the senescence burden, is configured as a negative prognostic factor for GBM stage. Furthermore, several anti-GBM therapies exist, such as temozolomide (TMZ) and etoposide (ETP), that unfortunately trigger senescence and the secretion of proinflammatory senescence-associated secretory phenotype (SASP) factors that are responsible for the improper burst of (i) tumorigenesis, (ii) cancer metastasis, (iii) immunosuppression, and (iv) tissue dysfunction. Thus, adjuvant therapies that limit senescence are urgently needed. The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene previously demonstrated a modulatory activity in restoring age-related immune dysfunction and in balancing the low-grade inflammatory status of elderly people. Based on the above findings, we tested LAV-BPIFB4 senotherapeutic effects on senescent glioblastoma U87-MG cells and on T cells from GBM patients. We interrogated SA-β-gal and HLA-E senescence markers, SASP factors, and proliferation and apoptosis assays. The results highlighted a LAV-BPIFB4 remodeling of the senescent phenotype of GBM cells, enhancement of their sensitivity to temozolomide and a selective reduction of the T cells’ senescence from GBM patients. Overall, these findings candidate LAV-BPIFB4 as an adjuvant therapy for GBM.

Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment

“…Senescent tumor cells that induce senescence in immune TME cells via secretion of SASP factors seem represent a more widespread phenomenon in aggressive tumors that are resistant to immune checkpoint blockade. In the most aggressive brain cancer, the Glioblastoma multiforme (GBM), patients displayed not only senescent tumor cells but also senescent immune cells in the tumor microenvironment and systemically in peripheral blood (27)(28)(29). In this context, a recent study by Puca et al could show that treatment of senescent glioblastoma U87-MG cells and senescent T-cells derived from peripheral blood of GBM patients with the senolytic drug longevity-associated variant (LAV) of the bactericidal/permeability-increasing foldcontaining family B member 4 (LAV-BPIFB4) reduced the senescent phenotype in both U87-MG cells and patient-derived PBMCs (29).…”

“…In the most aggressive brain cancer, the Glioblastoma multiforme (GBM), patients displayed not only senescent tumor cells but also senescent immune cells in the tumor microenvironment and systemically in peripheral blood (27)(28)(29). In this context, a recent study by Puca et al could show that treatment of senescent glioblastoma U87-MG cells and senescent T-cells derived from peripheral blood of GBM patients with the senolytic drug longevity-associated variant (LAV) of the bactericidal/permeability-increasing foldcontaining family B member 4 (LAV-BPIFB4) reduced the senescent phenotype in both U87-MG cells and patient-derived PBMCs (29). In our PC model, treatment of mice with a senolytic drug may represent a successful approach to reduce senescence in PC cells and in immune TME cells and prevent the development of cancer cells with stem cell characteristics.…”

“…Senescent tumor cells that induce senescence in immune TME cells via secretion of SASP factors seem represent a more widespread phenomenon in aggressive tumors that are resistant to immune checkpoint blockade. In the most aggressive brain cancer, the Glioblastoma multiforme (GBM), patients displayed not only senescent tumor cells but also senescent immune cells in the tumor microenvironment and systemically in peripheral blood ( 27 – 29 ). In this context, a recent study by Puca et al.…”

“…Induction of immunosenescence by senescent tumor cells is not limited to PC but could be a broader escape mechanism of aggressive tumors that are resistant to checkpoint inhibitor blockade. within the most aggressive malignant primary brain tumor, the Glioblastoma multiforme (GBM), several studies could show that patients with GBM have significantly more senescent cancer cells and more senescent T cells not only in the TME but also systemically in the peripheral blood compared with healthy age matched controls ( 27 – 29 ). Our results provide insights into a unique metastatic tumor site and shed new light on the mechanistics of senescence and immunosenescence within PC.…”

Effects of Human LAV-BPIFB4 Gene Therapy on the Epigenetic Clock and Health of Aged Mice

“…The BPIFB4 protein, implicated in activating homeostatic processes such as adaptive stress response and proteostasis, is found at high levels in the serum of long-living people and the LAV-BPIFB4 genetic variant has been associated with healthy aging and exceptional longevity [ 19 ]. In addition, the LAV-BPIFB4 gene therapy in mouse models has been proven to rescue the age-related endothelial dysfunction [ 20 ], reduce the progression of cardiovascular diseases [ 21 ], delay heart aging [ 22 ], and decrease the pool of senescent cells and senescence-associated inflammation [ 23 , 24 ]. In such pre-clinical studies, the LAV-BPIFB4 gene was delivered through an adeno-associated virus (AAV serotype 9) carrying a liver-specific promoter.…”