Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors

作者：Zhang, Peitao; Guan, Haixia; Yuan, Shukai; Cheng, Huili; Zheng, Jian; Zhang, Zhenlei; Liu, Yifan; Yu, Yang; Meng, Zhaowei; Zheng, Xiangqian; Zhao, Li^*

来源：Nature Communications, 2022, 13(1): 1588.

DOI：10.1038/s41467-022-29000-5

• UP-REGULATION
• E-CADHERIN
• TBX3
• EXPRESSION
• MELANOMA
• BRAF(V600E)
• ACTIVATION
• CARCINOMA
• CXCL1
• IMMUNOTHERAPY

MAPK signaling inhibitor (MAPKi) therapies show limited efficacy for advanced thyroid cancers despite constitutive activation of the signaling correlates with disease recurrence and persistence. Understanding how BRAF pathway stimulates tumorigenesis could lead to new therapeutic targets. Here, through genetic and pathological approaches, we demonstrate that BRAF(V600E) promotes thyroid cancer development by increasing myeloid-derived suppressor cells (MDSCs) penetrance. This BRAF(V600E)-induced immune suppression involves re-activation of the developmental factor TBX3, which in turn up-regulates CXCR2 ligands in a TLR2-NF kappa B dependent manner, leading to MDSCs recruitment into the tumor microenvironment. CXCR2 inhibition or MDSCs repression improves MAPKi therapy effect. Clinically, high TBX3 expression correlates with BRAF(V600E) mutation and increased CXCR2 ligands, along with abundant MDSCs infiltration. Thus, our study uncovers a BRAF(V600E)-TBX3-CXCLs-MDSCs axis that guides patient stratification and could be targeted to improve the efficacy of MAPKi therapy in advanced thyroid cancer patients. @@@ BRAF-V600E mutation is common in patients with papillary thyroid carcinoma (PTC) and has been associated with an aggressive phenotype. Here the authors show that the mutation supports cancer progression by reactivating the developmental factor TBX3 and promoting the recruitment of myeloid derived suppressive cells.

• 单位
  南方医科大学; 广东省人民医院