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 1

A CD138+ TAM subpopulation is identified and associated with immune evasion and poor prognosis in PDAC.

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A CD138+ TAM subpopulation is identified and associated with immune evas...
(A–C) Abundance of various immune cell types (A) and the proportions of activated cytotoxic and exhausted CD8+ T cells within CD8+ T cells, Treg cells among T cells (B), and CD138+ TAMs among macrophages (C). The analysis utilized mIHC data from 41 paired adjacent benign and tumor tissue samples collected from patients with PDAC in cohort 2. (D) Representative images of CD138+ macrophages in adjacent benign (n = 58) and tumor tissues (n = 103) from patients with PDAC in cohort 1. (E and F) Quantification of data from D, with graphs depicting the frequencies of CD138+ macrophages in CD68+ macrophages (E) and in CD45+ cells (F). (G) Correlation among the abundance of CD138+ TAMs, CD8+ T cells, activated cytotoxic CD8+ T cells, and Pan-CK+ tumor cells in tumor tissues from patients with PDAC in cohort 2 (n = 41). (H) Kaplan-Meier survival curves generated for the abundance of CD138+ TAMs calculated through multispectral analysis of tumor tissues from patients with PDAC in cohort 3. This analysis categorized patients into 2 groups: CD138+ TAM-high and CD138+ TAM-low (graph on the right), revealing median survival times of 9.5 and 12 months, respectively (P value = 0.0069, HR 1.685, 95% CI 1.098–2.584). (I) Flow cytometry images of CD138+ macrophages in the tumor tissues of spontaneous KPC mice. (J and K) Quantification of data from I, representing the frequencies of CD138+ macrophages in F4/80+ macrophages (J) and in CD45+ cells (K) (n = 8 per group). (L) Immunofluorescence microscopy images of tumors from spontaneous KPC mice showing the presence of CD138+ macrophages (white arrowheads). Scale bar: 10 μm. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by paired or unpaired 2-tailed Student’s t test (A–C, E, F, J, and K), by Pearson’s correlation analysis (G), and by log-rank analysis (H). Data represent mean ± SEM.