2026-04-23 国立がん研究センター,ナショナルセンター医療研究連携推進本部
＜関連情報＞
- https://www.ncc.go.jp/jp/information/researchtopics/2026/0423/index.html
- https://www.sciencedirect.com/science/article/pii/S0304383526001114
MIF-CD74経路は膵管腺癌の腫瘍微小環境におけるMDSCの浸潤を促進する MIF-CD74 axis facilitates MDSC infiltration in the tumor microenvironment of pancreatic ductal adenocarcinoma
Hironori Fukuda, Kosuke Arai, Eri Hashimoto, Keisuke Sekine, Yasuhito Arai, Nobuyoshi Hiraoka, Aya Hirata, Makiko Yamashita, Kenta Narumi, Ayaka Kikuchi, Eri Sawai, Yuria Sawada, Ayana Sunami, Yukihiro Mizoguchi, Ryoichi Sadahiro, Yukiko Aikawa, Yasuko Henmi, Genki Okumurai, Eri Sugiyama, Mami Takahashi…Kazunori Aoki
Cancer Letters Available online: 20 February 2026
DOI:https://doi.org/10.1016/j.canlet.2026.218348
Highlights
- The underlying mechanism of a strong immunosuppressive TME in PDAC remains unclear.
- MDSCs play a crucial role in creating an immunosuppressive TME.
- CD74+MDSCs infiltrate PDAC tissues through interaction with MIF produced by CAFs.
- Inhibition of MIF-CD74 interaction may improve the immunosuppressive condition.
Abstract
Immune checkpoint inhibitors show insufficient efficacy against pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment (TME) has a remarkable influence on responsiveness to cancer immunotherapy. The aim of this study was to investigate immunosuppressive characteristics of TME in PDAC tissues. The flow cytometry (FCM) of PDAC surgical specimens revealed that the profile of tumor-infiltrating leukocytes was classified into myeloid cell- and T-cell-dominant subtypes; the myeloid subtype was associated with poorer patient outcomes. Myeloid-derived suppressor cells (MDSCs) showed the highest hazard ratio among various myeloid cell types. Single-cell RNA sequencing and FCM revealed that most MDSCs, but not lymphocytes, in PDAC tissues characteristically express CD74. Macrophage migration inhibitory factor (MIF), a CD74 ligand, was highly expressed in cancer-associated fibroblasts (CAFs) and cancer cells. Spatial transcriptomics demonstrated that the MIF-CD74+ myeloid cell interaction was recognized in CAF-dominant areas in PDAC tissue. CAFs expressing immune suppressor molecules such as MFAP5 and LRRC15 were consistent with MIF+ CAFs. Furthermore, MIF+ CAFs enhanced the migratory activity of MDSCs and promoted MDSC induction and activation. In the murine model, MDSCs were significantly increased in MIF-expressing PDAC tumors, as were CD74+ M-MDSCs per M-MDSC, confirming in vivo interaction between CD74 and MIF. MDSCs play a crucial role in creating an immunosuppressive TME in PDAC; the MIF-CD74 axis drives interactions between MDSCs and CAFs.
