한빛사논문
- 조회590
Hyeok-Won An1,5, Sang Hyeok Seok1,5, Jong-Wan Kwon1, Anahita Dev Choudhury3, Jeong-Seop Oh2, Dominic C. Voon3,4, Dae-Yong Kim2, Jun Won Park1,6
1Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, 1 Kangwondaehak-gil, ChunCheon-si, Gangwon-do 24341, South Korea
2Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, South Korea
3Innovative Cancer Model Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
4Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
5These authors contributed equally
6Lead contact
Corresponding authors: Dominic C. Voon, Dae-Yong Kim, Jun Won Park
Abstract
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.
논문정보
- Research article
- 2022년 12월 (BRIC 등록일 2023-01-06)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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