ASMase is Essential for the Immune Response to Partial-Tumor Radiation Exposure.

IF 2.5 Q3 CELL BIOLOGY
Mickael Mathieu, Prerna R Nepali, James Russell, Hadi Askarifirouzjaei, Melis Baltaci, Simon N Powell, John Humm, Joseph O Deasy, Adriana Haimovitz-Friedman
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引用次数: 0

Abstract

Background/aims: Tumor response to radiation is thought to depend on the direct killing of tumor cells. Our laboratory has called this into question. Firstly, we showed that the biology of the host, specifically the endothelial expression of acid sphingomyelinase (ASMase), was critical in determining tumor radiocurability. Secondly, we have shown that the immune system can enhance radiation response by allowing a complete tumor control in hemi-irradiated tumors. In this paper, we focus on the integration of these two findings.

Methods: We used Lewis Lung Carcinoma (LLC) cells, injected in the flank of either: (i) ASMase knockout or (ii) WT of matched background (sv129xBl/6) or (iii) C57Bl/6 mice. Radiation therapy (RT) was delivered to 50% or 100% of the LLC tumor volume. Tumor response, immune infiltration (CD8+ T cells), ICAM-1, and STING activation were measured. Radiotherapy was also combined with methyl-cyclodextrin, to inhibit the ASMase-mediated formation of ceramide-enriched lipid rafts.

Results: We recapitulated our previous finding, namely that tumor hemi-irradiation was sufficient for tumor control in the LLC/C57Bl/6 model. However, in ASMase KO mice hemi-irradiation was ineffective. Likewise, pharmacological inhibition of ASMase significantly reduced the tumor response to hemi-irradiation. Further, we demonstrated elevated ICAM-1 expression, increased levels of CD8+ T cells, ICAM-1, and STING activation in tumors growing in C57Bl/6 mice, as well as the ASMase WT strain. However, no such changes were seen in tumors growing in ASMase KO mice.

Conclusion: ASMase and ceramide generation are necessary to mediate a radiation-induced anti-tumor immune response via STING activation.

ASMase对部分肿瘤辐射的免疫反应至关重要
背景/目的:肿瘤对辐射的反应被认为取决于对肿瘤细胞的直接杀伤。我们的实验室对此提出了质疑。首先,我们证明了宿主的生物学特性,特别是酸性鞘磷脂酶(ASMase)的内皮表达,是决定肿瘤放射可逆性的关键。其次,我们证明了免疫系统可以增强辐射反应,使半辐射肿瘤得到完全控制。在本文中,我们将重点讨论这两项发现的整合:我们使用刘易斯肺癌(LLC)细胞,在(i) ASMase基因敲除小鼠或(ii) 匹配背景的 WT(sv129xBl/6)或(iii) C57Bl/6小鼠的腹部注射。对LLC肿瘤体积的50%或100%进行放射治疗(RT)。测量肿瘤反应、免疫浸润(CD8+ T 细胞)、ICAM-1 和 STING 活化。放疗还与甲基环糊精联合使用,以抑制 ASMase 介导的神经酰胺富集脂质筏的形成:结果:我们再现了之前的发现,即在 LLC/C57Bl/6 模型中,肿瘤半照射足以控制肿瘤。然而,在 ASMase KO 小鼠中,半照射是无效的。同样,药理抑制 ASMase 也会显著降低肿瘤对半照射的反应。此外,我们还发现,在 C57Bl/6 小鼠和 ASMase WT 株系中生长的肿瘤中,ICAM-1 表达升高,CD8+ T 细胞、ICAM-1 和 STING 激活水平升高。然而,在 ASMase KO 小鼠体内生长的肿瘤中却未见此类变化:结论:ASMase和神经酰胺的生成是通过STING激活辐射诱导抗肿瘤免疫反应的必要条件。
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来源期刊
CiteScore
5.80
自引率
0.00%
发文量
86
审稿时长
1 months
期刊介绍: Cellular Physiology and Biochemistry is a multidisciplinary scientific forum dedicated to advancing the frontiers of basic cellular research. It addresses scientists from both the physiological and biochemical disciplines as well as related fields such as genetics, molecular biology, pathophysiology, pathobiochemistry and cellular toxicology & pharmacology. Original papers and reviews on the mechanisms of intracellular transmission, cellular metabolism, cell growth, differentiation and death, ion channels and carriers, and the maintenance, regulation and disturbances of cell volume are presented. Appearing monthly under peer review, Cellular Physiology and Biochemistry takes an active role in the concerted international effort to unravel the mechanisms of cellular function.
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