A CD138+ tumor-associated macrophage/Siglec-F+ neutrophil feed-forward loop promotes immune evasion in pancreatic cancer
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
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
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Research Article Gastroenterology Immunology Oncology

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

Abstract

Immune evasion is a major obstacle in pancreatic cancer therapy. Recent data implicate proinflammatory macrophages in the progression of pancreatic ductal adenocarcinoma (PDAC) and its therapeutic response. However, whether or which of the proinflammatory 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 proinflammatory and neutrophil-chemotactic activity, which undergo significant expansion in both patients with PDAC 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 feed-forward 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 suppressed 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

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Figure 3

The formation of CD138+ TAMs is induced via IL-34/syndecan-1 and PGE2/EP2 signaling.

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The formation of CD138+ TAMs is induced via IL-34/syndecan-1 and PGE2/EP...
(A) Representative flow cytometry images illustrating the expression levels of CD138, CXCL1, and SAA3 in F4/80+ cells from BMDM cultures treated with IL-34 and/or PGE2. (B and C) Quantification of data from A, showcasing the percentages of CD138+ (B) and CXCL1+SAA3+ (C) within the F4/80+ population (n = 3 per group). (D) Heatmap of the relative expression of genes synergized by IL-34 plus PGE2 in BMDM cultures. (E) GSEA of genes synergized by IL-34 plus PGE2, on genes ranked by their correlation with the fate probability of the monocyte-to-Sdc1+ TAM trajectory (left) and by log2FC between each monocyte/macrophage (Mono/Mph) subset versus other monocytes/macrophages (right). (F) Representative images showing the expression of CD138, CXCL1, and SAA3 in F4/80+ cells within tumor tissues from control or Ptger2-cKO mice bearing orthotopic KPCvector or KPCIl34-KO tumors. (G and H) Quantification of data from F, illustrating the percentages of CD138+ (G) and CXCL1+SAA3+ (H) within F4/80+ macrophages (n = 7 per group). (I) Flow cytometry images of CXCL1+SAA3+ macrophages in the cultures of BMDMs derived from control or Sdc1-cKO mice in the presence of IL-34 and PGE2. (J) Quantification of data from I, showing the percentages of CXCL1+SAA3+ within F4/80+ macrophages (n = 3 per group). (K) Representative images of CXCL1+SAA3+ macrophages in BMDM cultures treated with IL-34 and PGE2, with or without synstatin, a selective inhibitor of syndecan-1. (L) Quantification of data from K, highlighting the percentages of CXCL1+SAA3+ in F4/80+ macrophages (n = 3 per group). *P < 0.05, **P < 0.01, and ****P < 0.0001 by Kruskal-Wallis test with Dunn’s multiple-comparison test (G and H) and by unpaired 2-tailed Student’s t test (J and L). Data represent mean ± SEM.