Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells

Baghdadi, Muhammad; Wada, Haruka; Nakanishi, Sayaka; Abe, Hiroki; Han, Nanumi; Putra, Wira Eka; Endo, Daisuke; Watari, Hidemichi; Sakuragi, Noriaki; Hida, Kyoko; Kaga, Kichizo; Miyagi, Yohei; Yokose, Tomoyuki; Takano, Atsushi; Daigo, Yataro; Seino, Ken‐ichiro

doi:10.1158/0008-5472.can-16-1170

Cited by 155 publications

(161 citation statements)

References 51 publications

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“…Interleukin‐34 promotes the growth and metastasis of HCC through recruitment and infiltration of TAMs . Moreover, IL‐34 expression is known to be associated with therapeutic resistance in lung cancer and melanoma . Therefore, in this study, serum IL‐34 level could reflect hepatic fibrosis as well as tumor factors, and was associated with the prognosis of patients with non‐viral HCC.…”

Section: Discussionmentioning

confidence: 79%

High serum interleukin‐34 level is a predictor of poor prognosis in patients with non‐viral hepatocellular carcinoma

Noda

Kawaguchi

Korenaga

et al. 2019

Hepatology Research

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Aims We aimed to investigate the impact of interleukin (IL)‐34 and YKL‐40, regulators of hepatic fibrosis and tumor growth, on the prognosis of patients with non‐viral hepatocellular carcinoma (HCC). Methods We enrolled 159 non‐viral HCC patients (age, 70.8 ± 8.5 years; female/male, 43/116). Of these, 86 patients were alive and 73 patients had died at the censor time point. Serum IL‐34 and YKL‐40 levels were quantified by enzyme‐linked immunosorbent assay. Patients were stratified by the median level of serum IL‐34 to examine its effect on survival. Multivariate analysis and random forest analysis were used to evaluate the impact of IL‐34 and YKL‐40 on the prognosis of non‐viral HCC patients. Results Interleukin‐34 (hazard ratio [HR] 1.30; 95% confidence interval [CI], 1.13–1.49; P ≤ 0.01), tumor size (HR 1.63; 95% CI, 1.37–1.94; P ≤ 0.01), and tumor number (HR 1.53; 95% CI, 1.25–1.87; P ≤ 0.01) were independent predictive factors for survival. Furthermore, the survival rates were significantly lower in the high IL‐34 group than in the low IL‐34 group (5‐year survival rates, 34.7% vs. 59.8%, respectively; P < 0.05). In the random forest analysis for survival, IL‐34 was the third‐highest ranking factor, following tumor size and number. In a stratification analysis, serum α‐fetoprotein level and Fibrosis‐4 index were independent positive risk factors for high serum IL‐34 level. YKL‐40 was not associated with prognosis in either the multivariate or random forest analysis. Conclusion Interleukin‐34 was an independent factor for survival of non‐viral HCC patients. Interleukin‐34 might be associated with prognosis through tumor and hepatic fibrosis factors.

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Section: Discussionmentioning

confidence: 79%

High serum interleukin‐34 level is a predictor of poor prognosis in patients with non‐viral hepatocellular carcinoma

Noda

Kawaguchi

Korenaga

et al. 2019

Hepatology Research

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“…In this study, we collected diagnostic biopsy samples of lymphoma tissues from 135 patients with DLBCL ( 17 and keratinocytes of the skins (Figure 1a, left), the latter of which are known to highly express IL-34. 5,6 The lymph nodes showing reactive hyperplasia were negative for IL-34 expression (Figure 1a, right).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the percentage of IL-34 + cases in the aggressive ABC subtype was significantly higher than that in the favorable GCB subtype ( Table 2). 17 Thus, the higher percentage of IL-34 + cases in the ABC subtype might be explained at least in part by the NF-jB activation. 43,44 The constitutive activation of NF-jB is also required for IL-34 expression in the doxorubicin-resistant A549 lung cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…9 Similarly, the neutralising antibodies or small molecule inhibitors that target M-CSF signalling have been shown to affect tumor malignancy in several animal models. 17 Interestingly, we and others recently reported the IL-34 expression in haematological malignancies such as adult T-cell leukaemia/ lymphoma 18 and multiple myeloma. 17 Interestingly, we and others recently reported the IL-34 expression in haematological malignancies such as adult T-cell leukaemia/ lymphoma 18 and multiple myeloma.…”

Section: Introductionmentioning

confidence: 85%

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Expression of IL‐34 correlates with macrophage infiltration and prognosis of diffuse large B‐cell lymphoma

et al. 2019

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Objectives Infiltration of macrophages through the tyrosine kinase receptor CSF1R is a poor prognosis factor in various solid tumors. Indeed, these tumors produce CSF1R ligand, macrophage colony‐stimulating factor (M‐CSF) or interleukin‐34 (IL‐34). However, the significance of these cytokines, particularly, the newly discovered IL‐34 in haematological malignancies, is not fully understood. We therefore analysed the role of IL‐34 in diffuse large B‐cell lymphoma (DLBCL), the most common subtype of malignant lymphoma. Methods We analysed formalin‐fixed paraffin‐embedded lymphoma tissues of 135 DLBCL patients for the expression of IL‐34 and the number of macrophages, and the survival of these patients. The expression of IL‐34 in DLBCL cell lines and the activity of IL‐34 to induce the migration of monocytic cells were also characterised. Results Several lymphoma tissues showed a clear IL‐34 signal, and such signal was detectable in 36% of patients. DLBCL cell lines also expressed IL‐34. Interestingly, the percentage of IL‐34+ patients in the activated B‐cell subtype was significantly higher than that in the germinal centre B‐cell subtype. More interestingly, IL‐34+ patients showed shorter survival periods and higher number of macrophages in lymphoma tissues. The recruitment of monocytes is likely the first step for the higher macrophage density in the IL‐34+ lymphoma tissues. Indeed, IL‐34 induced the migration of monocytic cells. Conclusion Our results raise the possibility that IL‐34 in lymphoma tissues of DLBCL patients recruits monocytes, leading to the higher number of macrophages in the tissues and poor prognosis of patients. IL‐34 may be an additional therapeutic target of DLBCL.

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“…Cyclophosphamide treatment promotes infiltration of macrophages, enhances secretion of pro-inflammatory cytokines (IL-6 and IL-12), and suppresses production of pro-tumoral M2-related cytokines (IL-4, IL-10, and IL-13) [161][162]. As a self-protective mechanism against chemotherapies, chemo-resistant cancer cells secrete IL-34 which enhances their survival as well as promotes M2 polarization of TAMs to further reinforce immunosuppressive functions [163]. In addition, chemotherapy treatments may also increase intratumoral level of CXCL12, which serves as a chemotactic factor in recruiting TIE2 + CXCR4 + macrophages to the perivascular region of the tumor where they preferentially promote angiogenesis and tumor regrowth [113].…”

Section: Pharmacological Modulation Of Macrophages/tamsmentioning

confidence: 99%

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

Ngambenjawong

Gustafson

Pun

2017

Advanced Drug Delivery Reviews

642

484

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As an essential innate immune population for maintaining body homeostasis and warding off foreign pathogens, macrophages display high plasticity and perform diverse supportive functions specialized to different tissue compartments. Consequently, aberrance in macrophage functions contributes substantially to progression of several diseases including cancer, fibrosis, and diabetes. In the context of cancer, tumor-associated macrophages (TAMs) in tumor microenvironment (TME) typically promote cancer cell proliferation, immunosuppression, and angiogenesis in support of tumor growth and metastasis. Oftentimes, the abundance of TAMs in tumor is correlated with poor disease prognosis. Hence, significant attention has been drawn towards development of cancer immunotherapies targeting these TAMs; either depleting them from tumor, blocking their pro-tumoral functions, or restoring their immunostimulatory/tumoricidal properties. This review aims to introduce readers to various aspects in development and evaluation of TAM-targeted therapeutics in pre-clinical and clinical stages.

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Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells

Cited by 155 publications

References 51 publications

High serum interleukin‐34 level is a predictor of poor prognosis in patients with non‐viral hepatocellular carcinoma

High serum interleukin‐34 level is a predictor of poor prognosis in patients with non‐viral hepatocellular carcinoma

Expression of IL‐34 correlates with macrophage infiltration and prognosis of diffuse large B‐cell lymphoma

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

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