Immunodominant AH1 Antigen-Deficient Necroptotic, but Not Apoptotic, Murine Cancer Cells Induce Antitumor Protection
Immunodominant AH1 Antigen-Deficient Necroptotic, but Not Apoptotic, Murine Cancer Cells Induce Antitumor Protection
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DOI：
10.4049/jimmunol.1900072
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发表时间：
2020-02-15
影响因子：
4.4
通讯作者：
Vandenabeele, Peter
中科院分区：
文献类型：
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作者：
Aaes, Tania Love;Verschuere, Hanne;Vandenabeele, Peter
免疫原性细胞死亡（ICD）发生时，垂死的细胞释放细胞因子和损伤相关的分子模式，作为佐剂，并表达抗原，诱导特异性抗肿瘤免疫反应。ICD的研究主要是在调节细胞死亡途径的背景下，特别是半胱天冬酶介导的细胞凋亡标记内质网应激和钙网蛋白暴露，最近，也与受体相互作用蛋白激酶驱动的坏死性凋亡，而不受调节的细胞死亡，如意外坏死是非免疫原性的。重要的是，ICD研究中使用的鼠癌细胞系通常表达被免疫系统识别为肿瘤相关Ag的病毒衍生肽。然而，目前尚不清楚不同的细胞死亡途径如何影响癌细胞的新表位交叉呈递和Ag识别。我们使用预防性肿瘤疫苗接种模型，并观察到凋亡和坏死性结肠癌CT 26细胞都有效地免疫小鼠对抗表达相同免疫显性肿瘤Ag，AH 1的乳腺癌细胞系的攻击，但只有坏死性CT 26细胞会产生针对CT 26特异性新表位的免疫应答。通过CRISPR/Cas9基因组编辑，我们敲除了AH 1，发现只有坏死的CT 26细胞仍然能够保护小鼠免受肿瘤攻击。因此，在这项研究中，我们表明，内源性AH 1肿瘤抗原表达可以掩盖不同的细胞死亡途径诱导的免疫原性的强度，并在AH 1敲除后，坏死性凋亡比细胞凋亡在预防性肿瘤疫苗接种模型更具免疫原性。这项工作突出了坏死性凋亡作为治疗癌症中细胞凋亡的可能首选ICD形式。
Immunogenic cell death (ICD) occurs when a dying cell releases cytokines and damage-associated molecular patterns, acting as adjuvants, and expresses Ags that induce a specific antitumor immune response. ICD is studied mainly in the context of regulated cell death pathways, especially caspase-mediated apoptosis marked by endoplasmic reticulum stress and calreticulin exposure and, more recently, also in relation to receptor-interacting protein kinase-driven necroptosis, whereas unregulated cell death like accidental necrosis is nonimmunogenic. Importantly, the murine cancer cell lines used in ICD studies often express virally derived peptides that are recognized by the immune system as tumor-associated Ags. However, it is unknown how different cell death pathways may affect neoepitope cross-presentation and Ag recognition of cancer cells. We used a prophylactic tumor vaccination model and observed that both apoptotic and necroptotic colon carcinoma CT26 cells efficiently immunized mice against challenge with a breast cancer cell line that expresses the same immunodominant tumor Ag, AH1, but only necroptotic CT26 cells would mount an immune response against CT26-specific neoepitopes. By CRISPR/Cas9 genome editing, we knocked out AH1 and saw that only necroptotic CT26 cells were still able to protect mice against tumor challenge. Hence, in this study, we show that endogenous AH1 tumor Ag expression can mask the strength of immunogenicity induced by different cell death pathways and that upon knockout of AH1, necroptosis was more immunogenic than apoptosis in a prophylactic tumor vaccination model. This work highlights necroptosis as a possible preferred ICD form over apoptosis in the treatment of cancer.