A CD138+ tumor-associated macrophage-Siglec-F+ neutrophil feedforward loop promotes immune evasion in pancreatic cancer

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Abstract

Immune evasion is a major obstacle ahead of pancreatic cancer therapy. Recent data implicate pro-inflammatory macrophages in the progression of pancreatic ductal adenocarcinoma (PDAC) and its therapeutic response. However, whether or which of the pro-inflammatory macrophage subtypes play a crucial role in the immune escape of PDAC remains unclear. Here we identify a population of CD138+ tumor-associated macrophages (TAMs), characterized by their pro-inflammatory and neutrophil-chemotactic activity, which undergo significant expansion in both PDAC patients and mouse models. These cells are elicited by a local synergy between IL-34-syndecan-1 and PGE2-EP2 signaling and are associated with immune evasion and poor clinical outcomes in patients, while also promoting immune escape and disease progression in mouse models. Mechanistically, CD138+ TAMs establish a feedforward loop with immunosuppressive Siglec-F+ neutrophils, which exhibit elevated PGE2 expression, via the secretion of Saa3 and Cxcl1. Targeting CD138+ TAMs by disrupting IL-34-syndecan-1 signaling with anti-IL-34 neutralizing antibodies significantly suppresses PDAC progression, especially when combined with anti-PD-1 antibodies. Together, our study elucidates a CD138+ TAM-Siglec-F+ neutrophil axis that drives immune escape in PDAC and proposes a therapeutic strategy that integrates IL-34-syndecan-1 signaling blockade with anti-PD-1 immunotherapy for the treatment of PDAC.

Authors

Chao Wang, Qi Zhang, Jinyan Huang, Fangyu Lin, Danyang Zhao, Youling Mu, Junshuo Tong, Jinping Li, Yingjiqiong Liang, Tao Zeng, Fukang Shi, Hang Shen, Tingting Lu, Tingbo Liang