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 4

CD138+ TAMs facilitate the progression of PDAC by promoting tumor immune evasion.

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CD138+ TAMs facilitate the progression of PDAC by promoting tumor immune...
(A) Experimental approach utilized for the adoptive transfer of CD138+ or CD138– TAMs isolated from CD45.1+ orthotopic tumors into CD45.2+ orthotopic KPC mice. (B and C) Quantification of tumor weight in mice (B) and the number of Ki67+ cells per ×40 field in tumor sections (C) (n = 6 per group). HPF, high power field. (D) Overall survival probabilities of mice that received the adoptive transfer (n = 8 per group). (E) Quantification of the frequencies of effector cell subsets within CD45+ cells in tumor tissues (n = 6 per group). (F) Analysis of UMAP (left) and the proportions (right) of CD8+ T cell clusters in tumor tissues. (G) Heatmap of the relative expression of effector cytokines in tumor-infiltrating CD8+ T cells. (H) GSEA of the gene set related to IFN-γ production. (I) GSEA of pathways associated with CD8+ T cell proliferation and activation. (J) Quantification of tumor weight in mice (n = 9 per group). (K and L) Quantification of the number of Ki67+ cells (K) and the percentage of CC3+ area (L) per ×40 field in tumor sections (n = 6 per group). CC3, cleaved caspase-3. (M) Overall survival probabilities of control and Sdc1-cKO mice (n = 8 per group). (N) Quantification of the frequencies of effector cell subsets within CD45+ cells in tumor tissues (n = 9 per group). (O) Analysis of UMAP (left) and the proportions (right) of CD8+ T cell clusters in tumor tissues. (P) Heatmap of the relative expression of effector cytokines in tumor-infiltrating CD8+ T cells. (Q) GSEA of the gene set related to IFN-γ production. (R) GSEA of pathways associated with CD8+ T cell proliferation and activation. *P < 0.05, **P < 0.01, and ***P < 0.001 by Kruskal-Wallis test with Dunn’s multiple-comparison test (B and E), by log-rank analysis (D and M), and by unpaired 2-tailed Student’s t test (J–L and N). Data represent mean ± SEM.