癌相关成纤维细胞分泌的 DKK1 促进免疫抑制性肿瘤微环境与结直肠癌化疗耐药

Chemotherapy is the cornerstone of treatment for colorectal cancer (CRC).

However, acquired resistance can lead to a decrease in the efficiency of chemotherapy.

Here, we show that cancer-associated fibroblasts (CAFs) play a critical role in acquired resistance to chemotherapy. Treatment with 5-fluorouracil (5-FU), oxaliplatin, or SN38 (an active metabolite of irinotecan) increased DKK1 expression and secretion, activation of MEK/ERK, and upregulation of p53 in CAFs. Knockdown of p53 or inhibition of MEK/ERK blocked the increase in DKK1 expression induced by chemotherapeutic agents in CAFs. Consistently, elevated DKK1 and phospho-ERK levels were found in CAFs isolated from surgically resected samples of patients treated with neoadjuvant therapy compared with non-chemotherapy controls.

Treatment with recombinant DKK1 promoted the tumor immunosuppressive functions of CAFs, as noted by the increased expression of immunosuppressive cytokines and chemokines. Administration of 5-FU in vivo increased DKK1 levels in the plasma.

Treatment with anti-DKK1 neutralizing antibody blocked 5-FU increased DKK1, repressed myeloid-derived suppressor cell (MDSC) tumor infiltration, increased NK cell tumor infiltration, and concurrently enhanced the antitumor efficacy of 5-FU. The current study identified CAF-secreted DKK1 as a contributing factor to chemotherapy resistance.

Importantly, our findings provide evidence for targeting DKK1 to counteract chemotherapy resistance in CRC.