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 7

A feed-forward loop between CD138+ TAMs and Siglec-F+ neutrophils drives tumor immune evasion by inhibiting the antitumor effects of CD8+ T cells.

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A feed-forward loop between CD138+ TAMs and Siglec-F+ neutrophils drives...
(A) Representative images showing NET formation (white arrowheads) in Siglec-F+ and Siglec-F– neutrophils isolated from orthotopic tumors. Scale bar: 20 μm. (B) Quantification of data from A, calculating the percentage of the total area covered by the SYTOX Green+ region (n = 30 per group). (C) Plots depicting IFN-γ production by OT1 CD8+ T cells from cocultures of splenocytes from OT1 transgenic mice with either Siglec-F– or Siglec-F+ neutrophils sorted from orthotopic tumors. (D) Quantification of data from C (n = 3 per group). (E) Images depicting IFN-γ production by activated CD8+ T cells from cocultures involving CD8+ T cells derived from human peripheral blood and either tumor-infiltrating SIGLEC-8– or SIGLEC-8+ neutrophils in patients with PDAC. (F) Quantification of data from E (n = 3 per group). (G) Schematic illustrating the cocultures of splenocytes isolated from OT1 transgenic mice with BMDNs treated with CM derived from CD138+ or CD138– TAMs sorted from orthotopic tumors, as well as with CXCL1 and/or SAA3. (H and J) Plots displaying IFN-γ production by OT1 CD8+ T cells from the indicated coculture groups upon treatment with CM (H) or CXCL1 and/or SAA3 (J). (I) Quantification of data from H (n = 5 per group). (K) Quantification of data from J (n = 3 per group). (L) Quantification of PGE2 levels in CM derived from Siglec-F– and Siglec-F+ neutrophils sorted from orthotopic tumors (n = 3 per group). (M) Schematic illustrating the cultures of BMDMs upon treatment with CM derived from Siglec-F+ or Siglec-F– neutrophils sorted from orthotopic tumors. (N) Images showing the percentages of CD138+ macrophages in BMDM cultures treated with CM. (O) Quantification of data from N (n = 3 per group). *P < 0.05 and **P < 0.01 by unpaired 2-tailed Student’s t test (B, D, and F) and by Kruskal-Wallis test with Dunn’s multiple-comparison test (I and L). Data represent mean ± SEM.