Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, 1 Kangwondaehak-gil, ChunCheon-si, Gangwon-do 24341, South Korea.
Innovative Cancer Model Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
Cell Rep. 2022 Dec 27;41(13):111878. doi: 10.1016/j.celrep.2022.111878.
SMAD4 is frequently mutated and inactivated in human gastric cancer (GC). Although the epithelial cell-autonomous functions of Smad4 have been extensively studied, its contribution to tumor immunity is largely undetermined. Here, we report that the loss of Smad4 expression in GC cells endows them with the ability to evade tumor immunity. Unlike their Smad4-proficient counterparts, Smad4-deficient stomach organoids can evade host immunity to form tumors in immunocompetent mice. Smad4-deficient GC cells show expanded CD133 cancer stem-like cells while suppressing dendritic cell (DC) differentiation and cytotoxic T cells with granulocytic myeloid-derived suppressor cell (G-MDSC) accumulation through a secretome containing CXCL1. Moreover, Smad4 deficiency increases programmed cell death ligand-1 (PD-L1) and decreases 4-1BBL expressions, indicating a change in immunogenicity. Combinatorial immune checkpoint blockade (ICB) of anti-PD-L1 and anti-CTLA-4 or agonistic anti-4-1BB antibodies effectively treats ICB monotherapy-resistant Smad4-deficient allografts, exposing a specific vulnerability. Collectively, these data provide a rational basis for ICB strategies in treating advanced GC with Smad4 deficiency.
SMAD4 频繁发生突变并失活于人类胃癌（GC）中。尽管 Smad4 的上皮细胞自主功能已被广泛研究，但它对肿瘤免疫的贡献在很大程度上仍未确定。在这里，我们报告 GC 细胞中 Smad4 的缺失赋予了它们逃避肿瘤免疫的能力。与 Smad4 功能正常的细胞相比，缺乏 Smad4 的胃类器官能够逃避宿主免疫，在免疫功能正常的小鼠中形成肿瘤。缺乏 Smad4 的 GC 细胞表现出扩增的 CD133 癌症干细胞样细胞，同时通过包含 CXCL1 的分泌组抑制树突状细胞（DC）分化和细胞毒性 T 细胞，并伴有粒细胞髓样来源抑制细胞（G-MDSC）的积累。此外，Smad4 缺失增加了程序性细胞死亡配体-1（PD-L1）的表达，降低了 4-1BBL 的表达，表明免疫原性发生了变化。抗 PD-L1 和抗 CTLA-4 的联合免疫检查点阻断（ICB）或激动性抗 4-1BB 抗体可有效治疗 ICB 单药耐药的 Smad4 缺失同种异体移植物，暴露出一种特定的脆弱性。总的来说，这些数据为治疗 Smad4 缺失的晚期 GC 的 ICB 策略提供了合理的依据。
