衰老性 CAR T 细胞逆转衰老相关病理
- 作者列表："Amor, Corina","Feucht, Judith","Leibold, Josef","Ho, Yu-Jui","Zhu, Changyu","Alonso-Curbelo, Direna","Mansilla-Soto, Jorge","Boyer, Jacob A.","Li, Xiang","Giavridis, Theodoros","Kulick, Amanda","Houlihan, Shauna","Peerschke, Ellinor","Friedman, Scott L.","Ponomarev, Vladimir","Piersigilli, Alessandra","Sadelain, Michel","Lowe, Scott W.
Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment^ 1 , 2 . Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells^ 3 , 4 and has a beneficial role in wound-healing responses^ 5 , 6 . Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis^ 1 , 7 . Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity^ 1 , 2 , 8 – 10 . Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)^ 11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases. Chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein that is upregulated on senescent cells, eliminate senescent cells in vitro and in vivo and reduce liver fibrosis in mice.
细胞衰老的特征是稳定的细胞周期阻滞和调节组织微环境 ^ 1,2 的分泌程序。生理上，衰老作为一种肿瘤抑制机制，阻止癌前细胞 ^ 3,4 的扩增，并在伤口愈合反应 ^ 5,6 中发挥有益作用。在病理上，衰老细胞的异常聚集产生了炎症环境，导致慢性组织损伤，并导致疾病，如肝纤维化和肺纤维化，动脉粥样硬化，糖尿病和骨关节炎 ^ 1,7。因此，从小鼠受损组织中消除衰老细胞可改善这些病理的症状，甚至促进长寿 ^ 1,2，8-10。这里我们测试了靶向衰老细胞的嵌合抗原受体 (CAR) T 细胞可以是有效的衰老剂的治疗概念。我们鉴定尿激酶型纤溶酶原激活物受体 (uPAR)^ 11 作为衰老过程中广泛诱导的细胞表面蛋白，表明 uPAR 特异性 CAR T 细胞在体内外有效消融衰老细胞。靶向 uPAR 的 CAR T 细胞延长了用衰老诱导药物组合治疗的肺腺癌小鼠的存活时间,并恢复化学或饮食诱导肝纤维化的小鼠的组织稳态。这些结果确立了衰老 CAR T 细胞对衰老相关疾病的治疗潜力。嵌合抗原受体 (CAR) T 细胞靶向 uPAR，一种在衰老细胞上上调的细胞表面蛋白，在体内外消除衰老细胞，减轻小鼠肝纤维化。
METHODS:Purpose Given the paucity of reliable predictors of tumor recurrence, progression, or response to somatostatin receptor ligand (SRL) therapy in acromegaly, we attempted to determine whether preoperative MR image texture was predictive of these clinical outcomes. We also determined whether image texture could differentiate somatotroph adenomas from non-functioning pituitary adenomas (NFPAs). Methods We performed a retrospective study of patients with acromegaly due to a macroadenoma who underwent transsphenoidal surgery at our institution between 2007 and 2015. Clinical data were extracted from electronic medical records. MRI texture analysis was performed on preoperative non-enhanced T1-weighted images using ImageJ (NIH). Logistic and Cox models were used to determine if image texture parameters predicted outcomes. Results Eighty-nine patients had texture parameters measured, which were compared to that of NFPAs, while 64 of these patients had follow-up and were included in the remainder of analyses. Minimum pixel intensity, skewness, and kurtosis were significantly different in somatotroph adenomas versus NFPAs (area under the receiver operating characteristic curve, 0.7771, for kurtosis). Furthermore, those with a maximum pixel intensity above the median had an increased odds of IGF-I normalization on SRL therapy (OR 5.96, 95% CI 1.33–26.66), which persisted after adjusting for several potential predictors of response. Image texture did not predict tumor recurrence or progression. Conclusion Our data suggest that MRI texture analysis can distinguish NFPAs from somatotroph macroadenomas with good diagnostic accuracy and can predict normalization of IGF-I with SRL therapy.
METHODS::Growth hormone-secreting pituitary adenoma (GHPA), a benign endocrine tumor located in the base of the skull, results in acromegaly. In addition to the mass effect of the tumor itself in the sellar region, GHPA can lead to the overgrowth of almost every organ. Previous findings indicated that the processes underlying acromegaly were partly attributable to hyperactivity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. However, the mechanisms driving this syndrome remains largely unknown. Additionally, the roles of GHPA-derived exosomes, which contain functional microRNAs and proteins that manipulate target cell proliferation and differentiation in distal extremities, are also unknown. In this study, we demonstrated that GHPA exosomes promote bone formation in vitro and trabecula number in vivo. The mechanism of increased trabecula formation may be attributable to GHPA exosome-induced osteoblast proliferation via increased cell viability and DNA replication. We further discovered that exosomal hsa-miR-21-5p plays a distinct role from the GH/IGF-1 axis in these processes. Accordingly, the results of this study provide a novel mechanism whereby GHPA influences distal extremities and a new perspective for treating GHPA.
METHODS:BACKGROUND:Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM:To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS:Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS:Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION:1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION:NCT00647179.