Qadir Abdul S, Guégan Jean Philippe, Ginestier Christophe, Chaibi Assia, Bessede Alban, Charafe-Jauffret Emmanuelle, Macario Manon, Lavoué Vincent, Rouge Thibault de la Motte, Law Calvin, Vilker Jacob, Wang Hongbin, Stroup Emily, Schipma Matthew J, Bridgeman Bryan, Murmann Andrea E, Ji Zhe, Legembre Patrick, Peter Marcus E
Division Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Explicyte, Cours de l'Argonne, 33000 Bordeaux, France.
iScience. 2021 Oct 29;24(11):103348. doi: 10.1016/j.isci.2021.103348. eCollection 2021 Nov 19.
The apoptosis inducing receptor CD95/Fas has multiple tumorigenic activities. In different genetically engineered mouse models tumor-expressed CD95 was shown to be critical for cell growth. Using a combination of immune-deficient and immune-competent mouse models, we now establish that loss of CD95 in metastatic triple negative breast cancer (TNBC) cells prevents tumor growth by modulating the immune landscape. CD95-deficient, but not wild-type, tumors barely grow in an immune-competent environment and show an increase in immune infiltrates into the tumor. This growth reduction is caused by infiltrating NK cells and does not involve T cells or macrophages. In contrast, in immune compromised mice CD95 k.o. cells are not growth inhibited, but they fail to form metastases. In summary, we demonstrate that in addition to its tumor and metastasis promoting activities, CD95 expression by tumor cells can exert immune suppressive activities on NK cells, providing a new target for immune therapy.
凋亡诱导受体CD95/Fas具有多种致瘤活性。在不同的基因工程小鼠模型中，肿瘤表达的CD95对细胞生长至关重要。通过结合免疫缺陷和免疫健全的小鼠模型，我们现在证实转移性三阴性乳腺癌（TNBC）细胞中CD95的缺失通过调节免疫格局来阻止肿瘤生长。在免疫健全的环境中，缺乏CD95而非野生型的肿瘤几乎不生长，且肿瘤内免疫浸润增加。这种生长抑制是由浸润的自然杀伤（NK）细胞引起的，不涉及T细胞或巨噬细胞。相比之下，在免疫受损的小鼠中，CD95基因敲除细胞的生长不受抑制，但它们无法形成转移灶。总之，我们证明，除了其促进肿瘤和转移的活性外，肿瘤细胞表达的CD95还可对NK细胞发挥免疫抑制活性，为免疫治疗提供了一个新靶点。
